Imidazotriaines and Imidazopyrimidines as Kinase Inhibitors

ABSTRACT

The present invention is directed to imidazo[1,2-b][1,2,4]triazines and imidazo[1,2-a]pyrimidines, and pharmaceutical compositions thereof, which are inhibitors of kinases such as c-Met and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. Nos. 60/860,840, filedNov. 22, 2006; 60/861,459, filed Nov. 29, 2006, and 60/957,236, filedAug. 22, 2007, the disclosures of each of which are incorporated hereinby reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to imidazo[1,2-b][1,2,4]triazines andimidazo[1,2-a]pyrimidines, and pharmaceutical compositions thereof,which are inhibitors of kinases such as c-Met and are useful in thetreatment of cancer and other diseases related to the dysregulation ofkinase pathways.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are a group of enzymes that regulate diverse,important biological processes including cell growth, survival anddifferentiation, organ formation and morphogenesis, neovascularization,tissue repair and regeneration, among others. Protein kinases exerttheir physiological functions through catalyzing the phosphorylation ofproteins (or substrates) and thereby modulating the cellular activitiesof the substrates in various biological contexts. In addition to thefunctions in normal tissues/organs, many protein kinases also play morespecialized roles in a host of human diseases including cancer. A subsetof protein kinases (also referred to as oncogenic protein kinases), whendysregulated, can cause tumor formation and growth, and furthercontribute to tumor maintenance and progression (Blume-Jensen P et al,Nature 2001, 411(6835):355-365). Thus far, oncogenic protein kinasesrepresent one of the largest and most attractive groups of proteintargets for cancer intervention and drug development.

Protein kinases can be categorized as receptor type and non-receptortype. Receptor tyrosine kinases (RTKs) have an extracellular portion, atransmembrane domain, and an intracellular portion, while non-receptortyrosine kinases are entirely intracellular. RTK mediated signaltransduction is typically initiated by extracellular interaction with aspecific growth factor (ligand), typically followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity, and receptor transphosphorylation. Binding sites are therebycreated for intracellular signal transduction molecules and lead to theformation of complexes with a spectrum of cytoplasmic signalingmolecules that facilitate the appropriate cellular response such as celldivision, differentiation, metabolic effects, and changes in theextracellular microenvironment

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, includesEGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growthfactor (EGF), TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. Asecond family of RTKs, designated the insulin subfamily, includes theINS-R, the IGF-1R and the IR-R. A third family, the “PDGF” subfamily,includes the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, referred to as the FLK subfamily, encompassesthe Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), thefetal liver kinase 4 (FLK-4) and the fins-like tyrosine kinase 1(fit-1). Two other subfamilies of RTKs have been designated as the FGFreceptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily(c-Met, Ron and Sea). For a detailed discussion of protein kinases, seefor example, Blume-Jensen, P. et al., Nature. 2001, 411(6835):355-365,and Manning, G. et al., Science. 2002, 298(5600):1912-1934.

The non-receptor type of tyrosine kinases is also composed of numeroussubfamilies, including Src, Btk, Abl, Fak, and Jak. Each of thesesubfamilies can be further subdivided into multiple members that havebeen frequently linked to oncogenesis. The Src family, for example, isthe largest and includes Src, Fyn, Lck and Fgr among others. For adetailed discussion of these kinases, see Bolen JB. Nonreceptor tyrosineprotein kinases. Oncogene. 1993, 8(8):2025-31.

A significant number of tyrosine kinases (both receptor and nonreceptor)are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosinekinase inhibitors in cancer therapy. Clin. Biochem. 2004,37(7):618-35.). Clinical studies suggest that overexpression ordysregulation of tyrosine kinases may also be of prognostic value. Forexample, members of the HER family of RTKs have been associated withpoor prognosis in breast, colorectal, head and neck and lung cancer.Mutation of c-Kit tyrosine kinase is associated with decreased survivalin gastrointestinal stromal tumors. In acute myelogenous leukemia, Flt-3mutation predicts shorter disease free survival. VEGFR expression, whichis important for tumor angiogenesis, is associated with a lower survivalrate in lung cancer. Tie-1 kinase expression inversely correlates withsurvival in gastric cancer. BCR-Abl expression is an important predictorof response in chronic myelogenous leukemia and Src tyrosine kinase isan indicator of poor prognosis in all stages of colorectal cancer.

c-Met, a proto-oncogene, is a member of a distinct subfamily ofheterodimeric receptor tyrosine kinases which include Met, Ron, and Sea(Birchmeier, C. et al., Nat. Rev. Mol. Cell Biol. 2003, 4(12):915-925;Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26). The onlyhigh affinity ligand for c-Met is the hepatocyte growth factor (HGF),also known as scatter factor (SF). Binding of HGF to c-Met inducesactivation of the receptor via autophosphorylation resulting in anincrease of receptor dependent signaling. Both c-Met and HGF are widelyexpressed in a variety of organs, but their expression is normallyconfined to the cells of epithelial and mesenchymal origin,respectively. The biological functions of c-Met (or c-Met signalingpathway) in normal tissues and human malignancies such as cancer havebeen well documented (Christensen, J. G. et al., Cancer Lett. 2005,225(1):1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292).

HGF and c-Met are each required for normal mammalian development, andabnormalities reported in both HGF- and c-Met-null mice are consistentwith proximity of embryonic expression and epithelial-mesenchymaltransition defects during organ morphogenesis (Christensen, J. G. etal., Cancer Lett. 2005, 225(1):1-26). Consistent with these findings,the transduction of signaling and subsequent biological effects ofHGF/c-Met pathway have been shown to be important forepithelial-mesenchymal interaction and regulation of cell migration,invasion, cell proliferation and survival, angiogenesis, morphogenesisand organization of three-dimensional tubular structures (e.g. renaltubular cells, gland formation) during development. The specificconsequences of c-Met pathway activation in a given cell/tissue arehighly context-dependent.

Dysregulated c-Met pathway plays important and sometimes causative (inthe case of genetic alterations) roles in tumor formation, growth,maintenance and progression (Birchmeier, C. et al., Nat. Rev. Mol. Cell.Biol. 2003, 4(12):915-925; Boccaccio, C. et al., Nat. Rev. Cancer 2006,6(8):637-645; Christensen, J. G. et al., Cancer Lett. 2005,225(1):1-26). HGF and/or c-Met are overexpressed in significant portionsof most human cancers, and are often associated with poor clinicaloutcomes such as more aggressive disease, disease progression, tumormetastasis and shortened patient survival. Further, patients with highlevels of HGF/c-Met proteins are more resistance to chemotherapy andradiotherapy. In addition to the abnormal HGF/c-Met expression, c-Metreceptor can also be activated in cancer patients through geneticmutations (both germline and somatic) and gene amplification. Althoughgene amplification and mutations are the most common genetic alterationsthat have been reported in patients, the receptor can also be activatedby deletions, truncations, gene rearrangement, as well as abnormalreceptor processing and defective negative regulatory mechanisms.

The various cancers in which c-Met is implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical,cholangiocarcinoma, colorectal, esophageal, gastric, head and neck,kidney, liver, lung, nasopharygeal, ovarian, pancreas, prostate,thyroid); musculoskeletal sarcomas (e.g., osteosarcaoma, synovialsarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g.,MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma); hematopoieticmalignancies (e.g., multiple myeloma, lymphomas, adult T cell leukemia,acute myelogenous leukemia, chronic myeloid leukemia); and otherneoplasms (e.g., glioblastomas, astrocytomas, melanoma, mesothelioma andWilm's tumor (www.vai.org/met/; Christensen, J. G. et al., Cancer Lett.2005, 225(1):1-26).

The notion that the activated c-Met pathway contributes to tumorformation and progression and could be a good target for effectivecancer intervention has been further solidified by numerous preclinicalstudies (Birchmeier, C. et al., Nat. Rev. Mol. Cell Biol. 2003,4(12):915-925; Christensen, J. G. et al., Cancer Lett. 2005,225(1):1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292).For example, studies showed that the tpr-met fusion gene, overexpressionof c-met and activated c-met mutations all caused oncogenictransformation of various model cell lines and resulted in tumorformation and metastasis in mice. More importantly, significantanti-tumor (sometimes tumor regression) and anti-metastasis activitieshave been demonstrated in vitro and in vivo with agents thatspecifically impair and/or block HGF/c-Met signaling. Those agentsinclude anti-HGF and anti-c-Met antibodies, HGF peptide antagonists,decoy c-Met receptor, c-Met peptide antagonists, dominant negative c-Metmutations, c-Met specific antisense oligonucleotides and ribozymes, andselective small molecule c-Met kinase inhibitors (Christensen, J. G. etal., Cancer Lett. 2005, 225(1):1-26).

In addition to the established role in cancer, abnormal HGF/c-Metsignaling is also implicated in atherosclerosis, lung fibrosis, renalfibrosis and regeneration, liver diseases, allergic disorders,inflammatory and autoimmune disorders, cerebrovascular diseases,cardiovascular diseases, conditions associated with organtransplantation (Ma, H. et al., Atherosclerosis. 2002, 164(1):79-87;Crestani, B. et al., Lab. Invest. 2002, 82(8):1015-1022; Sequra-Flores,A. A. et al., Rev. Gastroenterol. Mex. 2004, 69(4)243-250; Morishita, R.et al., Curr. Gene Ther. 2004, 4(2)199-206; Morishita, R. et al.,Endocr. J. 2002, 49(3)273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens.2002, 11(1):23-30; Matsumoto, K. et al., Kidney Int. 2001,59(6):2023-2038; Balkovetz, D. F. et al., Int. Rev. Cytol. 1999,186:225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998,18(4)345-348; Koch, A. E. et al., Arthritis Rheum. 1996,39(9):1566-1575; Futamatsu, H. et al., Circ. Res. 2005, 96(8)823-830;Eguchi, S. et al., Clin. Transplant. 1999, 13(6)536-544).

Despite the important/causative roles that the c-Met pathway plays inthe above described human diseases including cancer, there are no c-Metinhibitors or antagonists that are currently available for treatingthese human disorders that associate with abnormal HGF/c-Met signaling.Therefore, there is a clear unmet medical need to develop new compoundsas inhibitors of c-Met and other kinases. The compounds, compositions,and pharmaceutical methods provided herein help meet this need.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds that areinhibitors of kinases, including receptor tyrosine kinases such as thoseof the Met subfamily, having Formula I:

or pharmaceutically acceptable salts thereof or prodrugs thereof,wherein constituent members are defined herein.

The present invention further provides compositions comprising acompound of Formula I, or pharmaceutically acceptable salt thereof, andat least one pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting activity ofa receptor or non-receptor tyrosine kinase comprising contacting thekinase with a compound of Formula I, or pharmaceutically acceptable saltthereof.

The present invention further provides methods of inhibiting theHGF/c-Met kinase signaling pathway in a cell comprising contacting thecell with a compound of Formula I, or pharmaceutically acceptable saltthereof.

The present invention further provides methods of inhibiting theproliferative activity of a cell comprising contacting the cell with acompound of Formula I, or pharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting tumorgrowth in a patient comprising administering to the patient atherapeutically effective amount of a compound of Formula I, orpharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting tumormetastasis in a patient comprising administering to the patient atherapeutically effective amount of a compound of Formula I, orpharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ina patient, wherein said disease is associated with dysregulation of theHGF/c-MET signaling pathway, comprising administering to the patient atherapeutically effective amount of a compound of Formula I, orpharmaceutically acceptable salt thereof.

The present invention further provides methods of treating cancer in apatient comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I, or pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds that areinhibitors of kinases, including receptor tyrosine kinases such as thoseof the Met subfamily, having Formula I:

or pharmaceutically acceptable salts thereof or prodrugs thereof,wherein:

A is N or CR³;

Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 —W—X—Y—Z;

Cy² is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′;

L¹ is (CR⁴R⁵)_(m), (CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(arylene)-(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)—(heterocycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heteroarylene)-(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)C(O)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)O(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)OC(O)(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)OC(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)NR⁶C(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), or (CR⁴R⁵)_(p)S(O)₂NR⁶(CR⁴R⁵)_(q), whereinsaid cycloalkylene, arylene, heterocycloalkylene, or heteroarylene isoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d), P(R)₂, P(OR^(e))₂,P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

L² is (CR⁷R⁸)_(r), (CR⁷R⁸)_(s)-(cycloalkylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(arylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(heterocycloalkylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(heteroarylene)-(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)C(O)(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)C(O)NR⁹(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)C(O)O(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)OC(O)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)OC(O)NR⁹(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR⁹C(O)NR⁹(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)S(O)NR⁷(CR⁸R⁹)_(t),(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t), or (CR⁷R⁸)_(s)S(O)₂NR⁹(CR⁷R⁸)_(t), whereinsaid cycloalkylene, arylene, heterocycloalkylene, or heteroarylene isoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy⁴, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1) NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(c1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R¹ is H or —W″—X″—Y″—Z″;

R² is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(A), SR^(A), C(O)R^(B), C(O)NR^(C)R^(D), C(O)OR^(A),OC(O)R^(B), OC(O)NR^(C)R^(D), NR^(C)R^(D), NR^(C)C(O)R^(B),NR^(C)C(O)NR^(C)R^(D), NR^(C)C(O)OR^(A), S(O)R^(B), S(O)NR^(C)R^(D),S(O)₂R^(B), NR^(C)S(O)₂R^(B), or S(O)₂NR^(C)R^(D);

R³ is H, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 5 C₁₋₆ haloalkyl, CN, NO₂, OR^(A),SR^(A), C(O)R^(B), C(O)NR^(C)R^(D), C(O)OR^(A), OC(O)R^(B),OC(O)NR^(C)R^(D), NR^(C)R^(D), NR^(C)C(O)R^(B), NR^(C)C(O)NR^(C)R^(D),NR^(C)C(O)OR^(A), S(O)R^(B), S(O)NR^(C)R^(D), S(O)₂R^(B),NR^(c)S(O)₂R^(B), and S(O)₂NR^(C)R^(D); wherein said cycloalkyl, aryl,heterocycloalkyl, heteroaryl, or C₁₋₆ alkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from Cy⁵, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN,NO₂, N₃, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)C(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

or R² and -L²-Cy² are linked together to form a group of formula:

wherein ring B is a fused aryl or fused heteroaryl ring, each optionallysubstituted with 1, 2, or 3-W′—X′—Y′—Z′;

R⁴ and R⁵ are independently selected from H, halo, OH, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, alkoxyalkyl, cyanoalkyl,heterocycloalkyl, cycloalkyl, C₁₋₆ haloalkyl, CN, and NO₂;

or R⁴ and R⁵ together with the C atom to which they are attached form a3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C₁₋₆ haloalkyl,CN, and NO₂;

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

R⁷ and R⁸ are independently selected from H, halo, OH, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, CN, and NO₂;

or R⁷ and R⁸ together with the C atom to which they are attached form a3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, eachoptionally substituted by 1, 2, or 3 substituent independently selectedfrom halo, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, CN, and NO₂;

R⁹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl;

W, W′, and W″ are independently absent or independently selected fromC₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO,CONR^(h), SO, SO₂, SONR^(h) and NR^(h)CONR^(i), wherein each of the C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionally substitutedby 1, 2 or 3 substituents independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, and C₂₋₈ dialkylamino;

X, X′, and X″ are independently absent or independently selected fromC₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene, wherein each of the C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2or 3 substituents independently selected from halo, CN, NO₂, OH, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₈ alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR^(j),C(O)NR^(h)R^(i), amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

Y, Y′, and Y″ are independently absent or independently selected fromC₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO,CONR^(h), SO, SO₂, SONR^(h), and NR^(h)CONR^(i), wherein each of theC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

Z, Z′, and Z″ are independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(e2)R^(d2), NR^(e2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g))NR^(c2)R^(d2),NR^(e2)C(═NR)NR^(c2)R^(d2), P(R)₂, P(OR^(e2))₂, P(O)R^(e2)R^(f2),P(O)OR^(e2)OR, S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2)NR^(e2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl,and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(e2)R^(d2),NR^(e2)R^(d2), NR^(e2)C(O)R^(b2), NR^(e2)C(O)NR^(e2)R^(d2),NR^(e2)C(O)OR^(a2), C(═NR⁹)NR^(c2)R^(d2), NR^(c2)C(═NR⁹)NR^(e2)R^(d2),P(R^(f2))₂, P(OR^(e2))₂, P(O)R^(e2)R^(f2))₂, P(O)OR^(e2)OR, S(O)R^(b2),S(O)NR^(e2)R^(d2), S(O)₂R^(b2), NR^(e2)S(O)₂R^(b2), andS(O)₂NR^(e2)R^(d2);

-   -   wherein two adjacent —W—X—Y—Z, together with the atoms to which        they are attached, optionally form a fused 4-20 membered        cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring,        each optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a3),        SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3),        C(═NR^(g))NR^(c3)R^(d3) NR^(c3)C(═NR^(g))NR^(c3)R^(d3),        S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),        S(O)₂NR^(c3)R^(d3), aryl, cycloalkyl, heteroaryl, and        heterocycloalkyl;    -   wherein two adjacent —W′—X′—Y′—Z′, together with the atoms to        which they are attached, optionally form a fused 4-20 membered        cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring,        each optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a3),        SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3),        C(═NR^(g))NR^(c3)R^(d3), NR³C(═NR^(g))NR^(c3)R^(d3), S(O)R^(b3),        S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),        S(O)₂NR^(c3)R^(d3) aryl, cycloalkyl, heteroaryl, and        heterocycloalkyl;    -   Cy³, Cy⁴, and Cy⁵ are independently selected from aryl,        cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally        substituted by 1, 2, 3, 4, or 5 substituents independently        selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a4), SR^(a4),        C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(g))NR^(c4)R^(d4), NR^(c4)C(═NR^(g))NR^(c4)R^(d4),        P(R^(f4))₂, P(OR^(c4))₂, P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        and S(O)₂NR^(c4)R^(d4);

R^(A) is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroarylis optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, and C₁₋₄ alkyl;

R^(B) is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄ alkyl;

R^(C) and R^(D) are independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄ alkyl;

or R^(C) and R^(D) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄ alkyl; R^(a),R^(a1), R^(a2), R^(a3), and R^(a4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; R^(b),R^(b1), R^(b2), R^(b3), and R^(b4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R^(c) and R^(d) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R^(c1) and R^(d1) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R^(c2) and R^(d2) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl,arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, whereinsaid C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a4), C(O)R^(b4), S(O)₂R^(b3), alkoxyalkyl, and alkoxyalkoxy;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl,heteroaryl, C(O)OR^(a4), C(O)R^(b4), S(O)₂R^(b3), alkoxyalkyl, andalkoxyalkoxy;

R^(c3) and R^(d3) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R^(c4) and R^(d4) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c4) and R^(d4) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R^(e), R^(e1), R^(e2), and R^(e4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, (C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;

R^(f), R^(f1), R^(f2), and R^(f4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl;

R⁹ is H, CN, and NO₂;

R^(h) and R^(i) are independently selected from H and C₁₋₆ alkyl; R^(J)is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl;

m is 0, 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

r is 0, 1, 2, 3, 4, 5, or 6;

s is 0, 1, 2, 3, or 4; and

t is 0, 1, 2, 3, or 4.

In some embodiments, when A is CH, then L¹ is other than CO or(CR⁴R⁵)_(u) wherein u is 1.

In some embodiments, when A is CH, then L¹ is other than(CR⁴R⁵)_(p)C(O)(CR⁴R⁵)_(q) or (CR⁴R⁵)_(v) wherein v is 1, 2, 3, 4, 5, or6.

In some embodiments, when A is CH, then L¹ is(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(arylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heterocycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heteroarylene)-(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)C(O)O(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)OC(O)(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)OC(O)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)NR⁶C(O)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(O)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), or(CR⁴R⁵)_(p)S(O)₂NR⁶(CR⁴R⁵)_(q), wherein said cycloalkylene, arylene,heterocycloalkylene, or heteroarylene is optionally substituted with 1,2, or 3 substituents independently selected from Cy³, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

In some embodiments, when A is CH, then L¹ is(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q), p is 0, q is 0.

In some embodiments, when A is N, then L¹ is(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q), p is 0, q is 0.

In some embodiments, A is N.

In some embodiments, A is CR³.

In some embodiments, A is CH.

In some embodiments, Cy¹ is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4, or 5 —W—X—Y—Z.

In some embodiments, Cy¹ is aryl optionally substituted by 1, 2, 3, 4,or 5 —W—X—Y—Z.

In some embodiments, Cy¹ is heteroaryl optionally substituted by 1, 2,3, 4, or 5 —W—X—Y—Z.

In some embodiments, Cy² is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′.

In some embodiments, Cy² is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′ wherein at least one ofsaid —W′—X′—Y′—Z′ is C(O)NR^(c2)R^(d2).

In some embodiments, Cy² is aryl optionally substituted by 1, 2, 3, 4,or 5 —W′—X′—Y′—Z′.

In some embodiments, Cy² is heteroaryl optionally substituted by 1, 2,3, 4, or 5 —W′—X′—Y′—Z′.

In some embodiments, Cy¹ is quinonlinyl optionally substituted by 1, 2,3, 4, or 5 —W—X—Y—Z.

In some embodiments, Cy¹ is quinolinyl.

In some embodiments, L¹ is (CR⁴R⁵)_(m),(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(arylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heterocycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heteroarylene)-(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q), or(CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), wherein said cycloalkylene, arylene,heterocycloalkylene, or heteroarylene is optionally substituted with 1,2, or 3 substituents independently selected from Cy³, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L¹ is (CR⁴R⁵)_(m),(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(arylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heterocycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heteroarylene)-(CR⁴R⁵)_(q), wherein said cycloalkylene,arylene, heterocycloalkylene, or heteroarylene is optionally substitutedwith 1, 2, or 3 substituents independently selected from Cy³, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN,NO₂, N₃, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR⁹)NR^(W)R^(d),NR^(c)C(═NR^(g))NR^(c)R^(d), P(R)₂, P(OR^(e))₂, P(O)R^(e)R^(f),P(O)OR^(e)OR^(f), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L¹ is (CR⁴R⁵)_(m) or(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q) wherein said cycloalkylene isoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d), P(R^(f))₂,P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L¹ is CH₂ or CH₂CH₂ or cycloalkylene.

In some embodiments, L¹ is CH₂ or cyclopropylene.

In some embodiments, L¹ is (CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(arylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heterocycloalkylene)-(CR⁴R⁵)_(q), or(CR⁴R⁵)_(p)-(heteroarylene)-(CR⁴R⁵)_(q), wherein said cycloalkylene,arylene, heterocycloalkylene, or heteroarylene is optionally substitutedwith 1, 2, or 3 substituents independently selected from Cy³, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN,NO₂, N₃, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d),NR^(c)C(═NR^(g))NR^(c)R^(d), P(R)₂, P(OR^(e))₂, P(O)R^(e)R^(f),P(O)OR^(e)OR^(f), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L is (CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q)wherein said cycloalkylene is optionally substituted with 1, 2, or 3substituents independently selected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L is cycloalkylene.

In some embodiments, L is cyclopropylene.

In some embodiments, L is (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q) or(CR⁴R⁵)_(p)S(CR⁴R⁵)_(q).

In some embodiments, L is O or S.

In some embodiments, L² is (CR⁷R⁸)_(r).

In some embodiments, L² is (CR⁷R⁸), and r is 0.

In some embodiments, L² is (CR⁷R⁸)_(r),(CR⁷R⁸)_(s)-(cycloalkylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(arylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(heterocycloalkylene)-(CR⁷R⁸)_(t), or(CR⁷R⁸)_(s)-(heteroarylene)-(CR⁷R⁸)_(t), wherein said cycloalkylene,arylene, heterocycloalkylene, or heteroarylene is optionally substitutedwith 1, 2, or 3 substituents independently selected from Cy⁴, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN,NO₂, N₃, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(e1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(e1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)C(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(e1)R^(d1).

In some embodiments, L² is (CR⁷R⁸)_(r),(CR⁷R⁸)_(s)-(cycloalkylene)-(CR⁷R⁸)_(t) or(CR⁷R⁸)_(s)-(arylene)-(CR⁷R⁸)_(t), wherein said cycloalkylene orarylene, is optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy⁴, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(e1)R^(d1), NR^(c1)R^(d1), NR^(e1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(e1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)C(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, L² is (CR⁷R⁸)_(s)-(cycloalkylene)-(CR⁷R⁸)_(t) or(CR⁷R⁸)_(s)-(arylene)-(CR⁷R⁸)_(t), wherein said cycloalkylene orarylene, is optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy⁴, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)C(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, L² is cycloalkylene or arylene.

In some embodiments, L² is arylene.

In some embodiments, Cy² is aryl optionally substituted by 1, 2, 3, 4,or 5 —W′—X′—Y′—Z′.

In some embodiments, Cy² is heteroaryl optionally substituted by 1, 2,3, 4, or 5 —W′—X′—Y′—Z′.

In some embodiments, Cy² is cycloalkyl optionally substituted by 1, 2,3, 4, or 5 —W′—X′—Y′—Z′.

In some embodiments, Cy² is heterocycloalkyl optionally substituted by1, 2, 3, 4, or 5 —W′—X′—Y′—Z′.

In some embodiments, R¹ is H.

In some embodiments, R² is H.

In some embodiments, R³ is H.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is H.

In some embodiments, R⁸ is H.

In some embodiments, R⁹ is H.

In some embodiments, —W—X—Y—Z is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2) NR^(c2)R^(d2), NR^(c2)C(O)R^(b)2,NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a)2, C(═NR^(g))NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R)₂, P(OR^(e2))₂, P(O)R^(e2)R²,P(O)OR^(e2)OR^(f2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl,and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR)NR^(c2)R^(d2), NR^(c2)C(═NR^(g))NR^(c2)R^(d2),P(R^(f2))₂, P(OR^(e2))₂, P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2).

In some embodiments, —W—X—Y—Z is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2) NR^(c2)R^(d2), NR^(c2)C(O)R^(b)2,NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g))NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f), P(O)OR^(e2)OR^(f2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR²S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2).

In some embodiments, —W—X—Y—Z is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN,NO₂, N₃, or OR^(a2).

In some embodiments, —W—X—Y—Z is OR^(a2).

In some embodiments, —W—X—Y—Z is methoxy.

In some embodiments, —W′—X′—Y′—Z′ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2) NR^(c2)R^(d2), NR^(c2)C(O)R^(b)2,NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g))NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R)₂, P(OR^(e2))₂, P(O)R^(e2)R^(f2),P(O)OR^(e2)OR, S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),NR^(c2)S(O)₂R^(b2) S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl, andheterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b)2, NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g))NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR)NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R^(f1))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),NR^(c2)S(O)₂R^(b2), or S(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, N₃, OR^(a2), or C(O)NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, N₃, or OR^(a2).

In some embodiments, —W′—X′—Y′—Z′ is halo or C(O)NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is C(O)NR^(c2)R^(d2).

In some embodiments, m is 1, 2, 3, 4, 5, or 6.

In some embodiments, the compounds of the invention have Formula IIa orIIb:

In some embodiments, the compounds of the invention have Formula III:

In some embodiments, the compounds of the invention have Formula VI:

In some embodiments, the compounds of the invention have Formula VIIa:

In some embodiments, the compounds of the invention have Formula VIIb:

In some embodiments, the compounds of the invention have Formula VIII:

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further intended that the compounds of the invention are stable.As used herein “stable” refers to a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and preferably capable of formulation into an efficacioustherapeutic agent.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms.

As used herein, the term “alkylyene” refers to a linking alkyl group.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, and the like.

As used herein, “alkenylene” refers to a linking alkenyl group.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “alkynylene” refers to a linking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “arylene” refers to a linking aryl group.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems, including spirocycles. In some embodiments, cycloalkylgroups can have from 3 to about 20 carbon atoms, 3 to about 14 carbonatoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkylgroups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2triple bonds. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, for example, benzo derivatives ofpentane, pentene, hexane, and the like. A cycloalkyl group having one ormore fused aromatic rings can be attached though either the aromatic ornon-aromatic portion. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized, for example, having an oxo or sulfidosubstituent. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,adamantyl, and the like.

As used herein, “cycloalkylene” refers to a linking cycloalkyl group.

As used herein, a “heteroaryl” group refers to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in aheteroaryl group can also be oxidized to form an N-oxo moiety. Examplesof heteroaryl groups include without limitation, pyridyl, N-oxopyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike. In some embodiments, the heteroaryl group has from 1 to about 20carbon atoms, and in further embodiments from about 3 to about 20 carbonatoms. In some embodiments, the heteroaryl group contains 3 to about 14,3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heteroarylene” refers to a linking heteroaryl group.

As used herein, “heterocycloalkyl” refers to a non-aromatic heterocyclewhere one or more of the ring-forming atoms is a heteroatom such as anO, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic(e.g., having 2, 3 or 4 fused rings) ring systems as well asspirocycles. Example “heterocycloalkyl” groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles. A heterocycloalkyl group havingone or more fused aromatic rings can be attached though either thearomatic or non-aromatic portion. Also included in the definition ofheterocycloalkyl are moieties where one or more ring-forming atoms issubstituted by 1 or 2 oxo or sulfido groups. In some embodiments, theheterocycloalkyl group has from 1 to about 20 carbon atoms, and infurther embodiments from about 3 to about 20 carbon atoms. In someembodiments, the heterocycloalkyl group contains 3 to about 20, 3 toabout 14, 3 to about 7, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3,or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl groupcontains 0 to 3 double bonds. In some embodiments, the heterocycloalkylgroup contains 0 to 2 triple bonds.

As used herein, “heterocycloalkylene” refers to a linkingheterocycloalkyl group.

As used herein, “arylcycloalkyl” refers to cycloalkyl group substitutedby an aryl group.

As used herein, “arylheterocycloalkyl” refers to a heterocycloalkylgroup substituted by an aryl group.

As used herein, “arylheteroaryl” refers to a heteroaryl groupsubstituted by an aryl group.

As used herein, “biaryl” refers to an aryl group substituted by anotheraryl group.

As used herein, “heteroarylcycloalkyl” refers to a cycloalkyl groupsubstituted by a heteroaryl group.

As used herein, “heteroarylheterocycloalkyl” refers to aheterocycloalkyl group substituted by a heteroaryl group.

As used herein, “heteroarylaryl” refers to an aryl group substituted bya heteroaryl group.

As used herein, “biheteroaryl” refers to a heteroaryl group substitutedby another heteroaryl group.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “halosulfanyl” refers to a sulfur group having one ormore halogen substituents. Example halosulfanyl groups includepentahalosulfanyl groups such as SFs.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “hydroxylalkyl” refers to an alkyl group substituted byOH.

As used herein, “cyanoalkyl” refers to an alkyl group substituted by CN.

As used herein, “alkoxyalkyl” refers to an alkyl group substituted by analkoxy group.

As used herein, “alkoxyalkoxy” refers to an alkoxy group substituted byalkoxy.

As used herein, “haloalkoxy” refers to an —O-(haloalkyl) group.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “heteroarylalkyl” refers to alkyl substituted byheteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted byheterocycloalkyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated.

Compounds of the present invention that contain asymmetricallysubstituted carbon atoms can be isolated in optically active or racemicforms. Methods on how to prepare optically active forms from opticallyactive starting materials are known in the art, such as by resolution ofracemic mixtures or by stereoselective synthesis. Many geometric isomersof olefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds of the invention, and salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which is was formed or detected. Partial separation caninclude, for example, a composition enriched in the compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compound of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

The novel compounds of the present invention can be prepared in avariety of ways known to one skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using themethods as hereinafter described below, together with synthetic methodsknown in the art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given; other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatograpy (HPLC) or thin layerchromatography.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Resolution ofracemic mixtures can also be carried out by elution on a column packedwith an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques as described below.

A series of imidazo[1,2-b][1,2,4]triazine derivatives of formula 10 canbe prepared by the methods outlined in Scheme 1. Alkylations of ester 1with haloalkyl (R⁴X or R⁵X, X═Cl, Br, I) using a suitable base such as,but not limit to, NaH, lithium diisopropylamine (LDA), sodiumbis(trimethylsilyl)amide (NaHMDS), or lithium bis(trimethylsilyl)amide(LiHMDS) can give the corresponding ester 2 which can be hydrolyzed tothe acid 3 with alkaline solution such as lithium hydroxide, sodiumhydroxide, or potassium hydroxide. Coupling of the acid 3 withN,O-dimethylamine hydrochloride in the presence ofbenzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate(BOP), or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(EDCI), or N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU), orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or N,N′-dicyclohexylcarbodiimide (DCC) can produce the amide 4which is reduced to the aldehyde 5 by lithium tetrahydroaluminate (LAH).Wittig's reaction of the aldehyde 5 with(methoxymethyl)(triphenyl)phosphonium bromide and a suitable base suchas NaH, lithium sodium bis(trimethylsilyl)amide (NaHMDS), or lithiumbis(trimethylsilyl)amide (LiHMDS) can give a methoxyethene derivative 6which can be converted to the aldehyde 7 by treatment with aqueous HClsolution. Reaction of chloro-aldehyde 8 which can be obtained from thealdehyde 7 by treatment with NCS with 2-aminotriazine 9 provideimidazo[1,2-b][1,2,4]triazine derivatives 10.

The 2-aminotriazine 9 can be prepared by the method outlined in Scheme2. Semicarbazide 13 can be prepared by reaction of the semicarbazidehydrochloride with oxo-acetal 12 which, in turn, can be obtained fromoxo-acetaldehyde 11 by treatment with triethylformate. Intramolecularring closure of 13 can afford the triazinone 14 which can be convertedto the corresponding chloride 15 by reflux with POCl₃ in an inertsolvent such as chloroform, 1,2-dichloroethane, or toluene in thepresence of a catalytic amount of dimethylformamide (DMF). Replacementof the chlorine in 15 with ammonia can yield 2-aminotriazine 9 which canbe converted to 10 by reaction with the chloride 8.

Alternatively, the triazinone 14 can be prepared according to theprocedure outlined in Scheme 3. The oxo-acetaldehyde 11 can betransformed to the corresponding oxo-oxime 16. Reaction of 16 withsemicarbazide can give the compound 17. Hydrolysis of the oxime in 17followed by intramolecular ring closure can afford compound 14.

Further alternatively, compound 14 can be prepared according to theprocedure outlined in Scheme 4. The acid ester 18 can be converted toalpha-halo ketone 20 by treatment with dimethylsulfoxonium methylide,generated by refluxing of trimethylsulfoxonium chloride with potassiumtert-butoxide in THF, followed by a cleavage reaction with anhydroushydrogen chloride at about 65° C. N-alkylation of α-halo ketone 20 withthe sodium salt of 2,4-thiazolidinedione can produce the N-substituted2,4-thiazolidinedione 22 which can be converted to dihydrotriazinone 23.Oxidation of 23 with suitable oxidants such sodium3-nitrobenzenesulfonate or tert-butylhypochlorite or DDQ can yield thetriazinone 14.

In a similar manner, the triazine 3 can be prepared by the methodsoutline in Scheme 5. Amide 25, obtained by coupling of the acid 24 withN,O-dimethylhydroxylamine in the presence of BOP or DCC, can beconverted to the corresponding ketone 27 by reaction with lithium agent26 which can be produced by treatment of 1,3-dithiane with n-butyllithium at low temperature. Reflux of the ketone 27 withthiosemicarbazide in an inert solvent such as ethanol or toluene in thepresence of an acid such as 4-toluenesulfonic acid can afford thecompound 28. Alkylation of compound 28 with methyl iodide in thepresence of a suitable base such as cesium carbonate, potassiumcarbonate, sodium carbonate or sodium hydroxide can give triazine 29which can be transformed to the compound 9. The triazine 3 can beprepared from 9 as previously described.

A series of triazine derivatives of formula 35 can be prepared accordingto the procedures outlined in Scheme 6. Amine derivative 32 can beobtained from the chloride 30 by treatment with ethylhydrazinecarbimidothioate hydrobromide followed by replacement withhydrazine. Reaction of 32 with acid chloride 8 can produce thetriazinone 33 which can be transformed to the corresponding chloride 34.Suzuki Coupling of 34 with ArB(OH)₂ give the triazine derivative 35.

A series of triazine derivatives of formula 47 can be prepared accordingto the procedures outlined in Scheme 7. Treatment of the acid 36 withthiosemicarbazide in the presence of base such as sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, or the likecan give the compound 37 which can convert to compound 38 by alkylationwith methyl iodide. Triazinone 39 can be obtained from 38 by replacementwith hydrazine followed by reaction with the chloride 8. Compound 39 canbe transformed to the corresponding chloride 40 by treatment with POCl₃or SOCl₂. Reaction of 40 with an appropriate amine can afford thetriazine derivative 41.

A series of triazine derivatives of formula 45 can be prepared accordingto the procedures outlined in Scheme 8. Suzuki coupling ofbromopyrimidine 43 with an arylboronic acid ArB(OH)₂ can give2-aminotriazine 44 which can react with chloro-aldehyde 8 to provide thetriazine derivative 35

The 2-aminotriazine 44 can be prepared by the method outlined in Scheme9. The 2-aminopyrimidine 44 can be obtained by heating a mixture of anenaminaldehyde 46 with guanine hydrochloride. Alternatively, Suzukicoupling of aminopyrimidinyl boronic acid 47 with aromatic halide Cy²-X(Cy² is an aromatic moiety and X═Cl, Br, I) provides the2-aminopyrimidine 44.

A series of cycloalkylcarboxylic acids formula 51 can be prepared by themethod outlined in Scheme 10. Mono-alkylation of alpha-substitutedmethyl 48 with an alkylenedihalide such as ethylene dibromide,1,3-dibromopropane, and 1,4-dibromobutane can provide mono-alkylatedproduct 49, followed by treatment with either 1) sodium hydride indimethylsuloxide (DMSO) or DMF or 2) lithium diisopropylamide (LDA) inTHF can provide the cycloalkylcarboxylic acid esters 50. Hydrolysis of50 in presence of base such as lithium hydroxide, sodium hydroxide,potassium hydroxide, or the like can give the corresponding acid 51.

Alternatively, a series of cycloalkylcarboxylic acids of formula 51 canbe prepared from the corresponding nitrile 52 as shown in Scheme 12.Alpha-substituted acetonitrile 52 can be treated with potassiumhydroxide and alkylenedihalides such as ethylene dibromide,1,3-dibromopropane, 1,4-dibromobutane, and the like to providesubstituted cycloalkylcarbonitriles 53, which can be followed byhydrolysis to afford the desired cycloalkylcarboxylic acid 51.

Methods of Use

Compounds of the invention can modulate activity of protein kinases.Example protein kinases modulated by the compounds of the inventioninclude RTKs of the HER subfamily (e.g., EGFR, HER2, HER3 and HER4), ofthe insulin subfamily (e.g., INS-R, the IGF-1R and the IR-R), of thePDGF subfamily (e.g., the PDGF alpha and beta receptors, CSFIR, c-kitand FLK-II), of the FLK subfamily (e.g., Kinase insert Domain-Receptorfetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) andthe fms-like tyrosine kinases 1 and 3 (flt-1 and fit-3)), of the FGFreceptor family (e.g., FGFR1, FGFR2, FGFR3 and FGFR4), of the Metsubfamily (e.g., c-Met, Ron amd Sea), and of the Src, Abl, and Jak(e.g., Jak1, Jak2, and Jak3) subfamilies. In some embodiments, thecompounds of the invention modulate activity of c-Met.

The term “modulate” is meant to refer to an ability to increase ordecrease activity of an enzyme or receptor. Modulation can occur invitro or in vivo. Modulation can further occur in a cell. Accordingly,compounds of the invention can be used in methods of modulating aprotein kinase, such as an RTK, by contacting the enzyme (or cell orsample containing the enzyme) with any one or more of the compounds orcompositions described herein.

In some embodiments, compounds of the present invention can act asinhibitors of one or more protein kinases. In some further embodiments,compounds of the invention can be used in methods of inhibiting an RTKof the Met or FLK subfamilies. In yet further embodiments, the compoundsof the invention can be used in methods of inhibiting c-Met, KDR, orfit-3 kinase. In yet further embodiments, the compounds of the inventioncan be used as inhibitors c-Met. In yet further embodiments, thecompounds of the invention are selective inhibitors of c-Met.

Treatment of a cell (in vitro or in vivo) that expresses a proteinkinase with a compound of the invention can result in inhibiting theligand/kinase signaling pathway and inhibiting downstream events relatedto the signaling pathway such as cellular proliferation and increasedcell motility. For example, the compounds of the invention can blockand/or impair the biochemical and biological processes resulting fromc-Met pathway activation, including, but not limited to, c-Met kinaseactivation (e.g. c-Met phosphorylation) and signaling (activation andrecruitment of cellular substrates such as Gab 1, Grb2, She and c-Cb1and subsequent activation of a number of signal transducers includingPI-3 kinase, PLC-γ, STATs, ERK1/2 and FAK), cell proliferation andsurvival, cell motility, migration and invasion, metastasis,angiogenesis, and the like. Thus, the present invention further providesmethods of inhibiting a ligand/kinase signaling pathway such as theHGF/c-Met kinase signaling pathway in a cell by contacting the cell witha compound of the invention. The present invention further providesmethods of inhibiting proliferative activity of a cell or inhibitingcell motility by contacting the cell with a compound of the invention.

The present invention further provides methods of treating diseasesassociated with a dysregulated kinase signaling pathway, includingabnormal activity and/or overexpression of the protein kinase, in anindividual (e.g., patient) by administering to the individual in need ofsuch treatment a therapeutically effective amount or dose of a compoundof the present invention or a pharmaceutical composition thereof. Insome embodiments, the dysregulated kinase is of the Met family (e.g.,c-Met, Ron, or Sea). In some embodiments, the dysregulated kinase isoverexpressed in the diseased tissue of the patient. In someembodiments, the dysregulated kinase is abnormally active in thediseased tissue of the patient. Dysregulation of c-Met and the HGF/c-Metsignaling pathway is meant to include activation of the enzyme throughvarious mechanisms including, but not limited to, HGF-dependentautocrine and paracrine activation, c-met gene overexpression andamplification, point mutations, deletions, truncations, rearrangement,as well as abnormal c-Met receptor processing and defective negativeregulatory mechanisms.

In some embodiments, the compounds of the invention are useful intreating diseases such as cancer, atherosclerosis, lung fibrosis, renalfibrosis and regeneration, liver disease, allergic disorder,inflammatory disease, autoimmune disorder, cerebrovascular disease,cardiovascular disease, or condition associated with organtransplantation. In further embodiments, the compounds of the inventioncan be useful in methods of inhibiting tumor growth or metastasis of atumor in a patient.

Example cancers treatable by the methods herein include bladder cancer,breast cancer, cervical cancer, cholangiocarcinoma cancer, colorectalcancer, esophageal cancer, gastric cancer, head and neck cancer, cancerof the kidney, liver cancer, lung cancer, nasopharygeal cancer, ovariancancer, pancreatic cancer, prostate cancer, thyroid cancer,osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma,leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult Tcell leukemia, acute myelogenous leukemia, chronic myeloid leukemia.glioblastoma, astrocytoma, melanoma, mesothelioma, or Wilm's tumor, andthe like.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a compound of the invention with a protein kinaseincludes the administration of a compound of the present invention to anindividual or patient, such as a human, as well as, for example,introducing a compound of the invention into a sample containing acellular or purified preparation of the protein kinase.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, chemotherapeutics, anti-cancer agents, cytotoxicagents, or anti-cancer therapies (e.g., radiation, hormone, etc.), canbe used in combination with the compounds of the present invention fortreatment of the diseases, disorders or conditions described herein. Theagents or therapies can be administered together with the compounds ofthe invention (e.g., combined into a single dosage form), or the agentsor therapies can be administered simultaneously or sequentially byseparate routes of administration.

Suitable anti-cancer agents include kinase inhibiting agents includingtrastuzumab (Herceptin), imatinib (Gleevec), gefitinib (Iressa),erlotinib hydrochloride (Tarceva), cetuximab (Erbitux), bevacizumab(Avastin), sorafenib (Nexavar), sunitinib (Sutent), and RTK inhibitorsdescribed in, for example, WO 2005/004808, WO 2005/004607, WO2005/005378, WO 2004/076412, WO 2005/121125, WO 2005/039586, WO2005/028475, WO 2005/040345, WO 2005/039586, WO 2003/097641, WO2003/087026, WO 2005/040154, WO 2005/030140, WO 2006/014325, WO2005/070891, WO 2005/073224, WO 2005/113494, and US Pat. App. Pub. Nos.2005/0085473, 2006/0046991, and 2005/0075340.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (Taxol™), mithramycin, deoxyco-formycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).Further antibody therapeutics include antibodies to tyrosine kinasesand/or their ligands such as anti-HGF antibodies and/or anti-c-Metantibodies. The term “antibody” is meant to include whole antibodies(e.g., monoclonal, polyclonal, chimeric, humanized, human, etc.) as wellas antigen-binding fragments thereof.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Other anti-cancer agents include anti-cancer vaccines such as dendriticcells, synthetic peptides, DNA vaccines and recombinant viruses.

Methods for the safe and effective administration of most of the aboveagents are known to those skilled in the art. In addition, theiradministration is described in the standard literature. For example, theadministration of many of the chemotherapeutic agents is described inthe “Physicians' Desk Reference” (PDR, e.g., 1996 edition, MedicalEconomics Company, Montvale, N.J.), the disclosure of which isincorporated herein by reference as if set forth in its entirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which is acombination of a compound of the invention and a pharmaceuticallyacceptable carrier. These compositions can be prepared in a manner wellknown in the pharmaceutical art, and can be administered by a variety ofroutes, depending upon whether local or systemic treatment is desiredand upon the area to be treated. Administration may be topical(including ophthalmic and to mucous membranes including intranasal,vaginal and rectal delivery), pulmonary (e.g., by inhalation orinsufflation of powders or aerosols, including by nebulizer;intratracheal, intranasal, epidermal and transdermal), ocular, oral orparenteral. Methods for ocular delivery can include topicaladministration (eye drops), subconjunctival, periocular or intravitrealinjection or introduction by balloon catheter or ophthalmic insertssurgically placed in the conjunctival sac. Parenteral administrationincludes intravenous, intraarterial, subcutaneous, intraperitoneal orintramuscular injection or infusion; or intracranial, e.g., intrathecalor intraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral adminstration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlable, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the protein kinase targetin tissue samples, including human, and for identifying kinase ligandsby inhibition binding of a labeled compound. Accordingly, the presentinvention includes kinase enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe compounds of the invention. An “isotopically” or “radio-labeled”compound is a compound of the invention where one or more atoms arereplaced or substituted by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number typically found in nature(i.e., naturally occurring). Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ²H (also written as D for deuterium), ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro IDO enzyme labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the enzyme. Accordingly, the ability of atest compound to compete with the radio-labeled compound for binding tothe enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of diseases, such as cancer andother diseases referred to herein, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, or pharmaceuticallyacceptable salt thereof. Such kits can further include, if desired, oneor more of various conventional pharmaceutical kit components, such as,for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof c-Met according to one or more of the assays provided herein.

EXAMPLES

Experimentals for compounds of the invention are provided below. In someinstances, the crude product is a mixture of regioisomers. Typically,these isomers are separated on a preparative scale by high performanceliquid chromatography (HPLC) or flash chromatography (silica gel) asindicated in the Examples. Typical preparative reverse-phase highperformance liquid chromatography (RP-HPLC) column conditions are asfollows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: 0.1% TFA in acetonitrile; the flow rate is 30 ml/m, theseparating gradient is optimized for each compound using the CompoundSpecific Method Optimization protocol as described in the literature[“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)].

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B: 0.15%NH₄OH in acetonitrile; the flow rate was 30 ml/m, the separatinggradient is optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature[“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)].

The separated isomers are typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity under the followingconditions: Instrument; Agilent 1100 series, LC/MSD, Column: WatersSunfire™ C₁₈ 5 μm, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: 0.025% TFA in acetonitrile; gradient 2% to 80%of B in 3 min with flow rate 1.5 mL/min. Retention time (R_(t)) data inthe Examples refer to these analytical LC/MS conditions unless otherwisespecified.

Example 1:2-(4-Fluorophenyl)-7-(4-methoxybenzyl)imidazo[1,2-b][1,2,4]triazine

Step 1. 2,2-Diethoxy-1-(4-fluorophenyl)ethanone

A mixture of 1-(4-fluorophenyl)-2,2-dihydroxyethanone (4.0 g, 0.024mol), ethyl orthoformate (7.3 g, 49 mmol), and p-toluenesulfonic acidmonohydrate (200 g, 1.05 mol) in dichloromethane (50 mL) was refluxedfor 40 min. After cooling to room temperature (RT), the mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography eluting with dichloromethane to give the desired product(5.2 g). ¹H-NMR (300 MHz, CDCl₃): 8.18-8.25 (m, 2H), 7.08-7.16 (m, 2H),5.18 (s, 1H), 3.58-3.82 (m, 4H), 1.25 (t, J=7.0 Hz, 6H).

Step 2. 6-(4-Fluorophenyl)-1,2,4-triazin-3(2H)-one

A mixture of 2,2-diethoxy-1-(4-fluorophenyl)ethanone (5.2 g, 23 mmol),semicarbazide hydrochloride (2.6 g, 24 mmol) in ethanol (50 mL) wasstirred overnight at ambient temperature and then heated to 80° C. for 5hours. The reaction mixture was concentrated and the resulting residuewas dissolved in acetic acid (50 mL) which was heated to 130° C. for 6h. After cooling, the mixture was concentrated under reduced pressure.The residue was triturated with ethyl ether, filtered, and washed withdiethyl ether and then hexanes. The crystalline material was collectedand dried under high vacuum to give the desired product. (4.2 g, 96%)LCMS: (M+H)=192.1.

Step 3. 3-Chloro-6-(4-fluorophenyl)-1,2,4-triazine

A mixture of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (1.0 g, 5.23mmol) and phosphoryl chloride (8.0 mL) in chloroform (5.0 mL) was heatedunder reflux conditions overnight. After cooling, the volatiles wereremoved under reduced pressure. The residue was dissolved indichloromethane (60 mL) and was poured into ice with stirring. Themixture was neutralized with aqueous 2N potassium carbonate and filteredthrough a pad of Celite. The organic layer was separated and the aqueouslayer was extracted with dichloromethane (3×20 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by flash chromatographyto give the desired product. (600 mg, 54.6%)¹H-NMR (300 MHz, CDCl₃):8.88 (s, 1H), 8.06-8.12 (m, 2H), 7.06-7.14 (m, 2H). LCMS:(M+H)=210.1/212.1.

Step 4. 6-(4-Fluorophenyl)-1,2,4-triazin-3-amine

Ammonia gas was bubbled through a solution of3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (600 mg, 0.0029 mol) intetrahydrofuran (8 mL) for 5 min at −40° C. The reaction mixture wassealed and heated at 50° C. for 2 hours. The mixture was concentratedunder reduced pressure to yield the desired product (550 mg) which wasdirectly used in the next step without further purification. LCMS:(M+H)=209.1.

Step 5. 3-(4-Methoxyphenyl)propanal

A solution of dimethyl sulfoxide (5.1 mL) in dichloromethane (10 ml) wasadded to a stirred solution of oxalyl chloride (3.0 mL, 36 mmol) indichloromethane (40 ml) at −78° C. over 30 min. Upon completion of theaddition, the mixture was stirred at −78° C. for 5 min, followed byaddition of a solution of 4-methoxybenzenepropanol (3.0 g, 18 mmol) indichloromethane (20 ml) at −78° C. over 30 min. The resulting mixturewas stirred at −78° C. for 40 min. Next, triethylamine (15 mL, 110 mmol)was added dropwise over 10 min. The resulting mixture was allowed towarm to 0° C. and stirred at this temperature for 1 hour. It was dilutedwith dichloromethane (30 mL) and quenched with water (15 mL). Theorganic extracts were separated, washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography eluting with ethylacetate in hexanes (gradient: 3 min: 0/100 to 23 min: 20/80) to affordthe desired product (1.50 g, 51%).

Step 6. 2-Chloro-3-(4-methoxyphenyl)propanal

N-Chlorosuccinimide (980 mg, 0.0073 mol) was added to a mixture of3-(4-methoxyphenyl)propanal (1.0 g, 6.1 mmol) and D-proline (40 mg, 0.3mmol) in dichloromethane (10 mL, 200 mmol) at 0° C. The reaction mixturewas warmed to RT after 1 h, quenched with water, and extracted withdichloromethane. The organic extracts were washed with brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography eluting with ethylacetate in hexanes to give the desired product (860 mg). ¹H NMR (400MHz, CDCl₃): 9.52 (s, 1H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.36 (m, 1H),3.80 (s, 3H), 3.32 (m, 1H), 3.02 (m, 1H).

Step 7.2-(4-Fluorophenyl)-7-(4-methoxybenzyl)imidazo[1,2-b][1,2,4]triazine

A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine hydrochloride (50mg, 0.2 mmol) and 2-chloro-3-(4-methoxyphenyl)propanal (48 mg, 0.24mmol) in tert-amyl alcohol (1 mL) was heated at 130° C. for 4 h. Aftercooling, the mixture was purified by preparative HPLC to afford thedesired product. (7.1 mg) LCMS: (M+H)=335.1.

Example 2:2-(4-Fluorophenyl)-7-[1-(4-methoxyphenyl)cyclopropyl]imidazo[1,2-b]-[1,2,4]-triazine

Step 1. 1-Methoxy-4-1-[(E)-2-methoxyvinyl]cyclopropylbenzene

1.0 M of Potassium tert-butoxide in tetrahydrofuran (THF) (6.8 mL, 6.8mmol) was slowly added to a suspension ofchloro(methoxymethyl)triphenylphosphorane (2.3 g, 6.8 mmol) in THF (6.0mL, 74 mmol) at −10° C., and then the mixture was stirred at ambienttemperature for 1 h. 1-(4-methoxyphenyl)cyclopropanecarbaldehyde (300mg, 1.7 mmol) in THF (2.0 mL) was then added dropwise to the reactionmixture at 0° C., and stirred at RT for 1 hour. The mixture was filteredthrough a pad of silica gel eluting with dichloromethane. The filtratewas concentrated under reduced pressure. The residue was purified byflash chromatography eluting with ethyl acetate in hexanes (0-10%) toafford the desired product.

Step 2. [1-(4-Methoxyphenyl)cyclopropyl]acetaldehyde

1N HCl (3.0 mL) was added to a solution of1-methoxy-4-1-[(E)-2-methoxyvinyl]cyclopropylbenzene (350 mg, 1.7 mmol)in tetrahydrofuran (5.0 mL). The mixture was stirred at ambienttemperature for 6 hours, and then concentrated hydrochloric acid (0.2mL) was added. The mixture was stirred overnight, diluted with water,and extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography eluting with ethylacetate in hexanes (0-10%) to afford the desired product. LCMS:(M+H)=190.9.

Step 3. Chloro[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde

L-Proline (10 mg, 0.1 mmol) was added to a solution of[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (100 mg, 0.53 mmol) inchloroform (1 mL) at 0° C. followed by addition of N-chlorosuccinimide(84 mg, 0.63 mmol). The reaction mixture was stirred at ambienttemperature for 2 h. The mixture was diluted with hexanes and filtered.The filtrate was concentrated under reduced pressure and the residue waspurified by flash chromatography eluting with ethyl acetate in hexanes(0-10%) to afford the desired product.

Step 4.2-(4-Fluorophenyl)-7-[1-(4-methoxyphenyl)cyclopropyl]imidazo[1,2-b]-[1,2,4]-triazine

A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine (20.1 mg, 0.106mmol) and chloro[1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (53 mg,0.24 mmol) in isopropyl alcohol (0.6 mL) was heated to 90° C. overnight.After cooling, the mixture was diluted with methanol and was purified bymass-guided RP-HPLC to afford the desired product. LCMS: (M+H)=361.1.

Example 3:6-(1-(2-(4-Fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)cyclopropyl)quinoline

This compound was prepared using procedures analogous to those forExample 2. LCMS: (M+H)=382.0.

Example 4:6-(4-Fluorophenyl)-3-(4-methoxybenzyl)imidazo[1,2-a]pyrimidine

Step 1. 2-Chloro-5-(4-fluorophenyl)pyrimidine

A mixture of 5-bromo-2-chloropyrimidine (500 mg, 2 mmol),4-fluorophenylboronic acid (430 mg, 3.1 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (1:1) (210 mg, 0.26 mmol) and potassiumcarbonate (1.8 g, 13 mmol) in 1,4-dioxane (6 mL) was irradiated undermicrowave at 120° C. for 30 min. After cooling, the solvent wasevaporated. The residue was purified by flash chromatography elutingwith ethyl acetate in hexanes to give the desired product. (376 mg)LCMS: (M+H)=209.0.

Step 2. 5-(4-Fluorophenyl)pyrimidin-2-amine

2-Chloro-5-(4-fluorophenyl)pyrimidine (376 mg) in 7M of ammonia inmethanol (10 mL) in a sealed tube was heated at 50° C. overnight. Afterconcentration, the product was obtained (360 g) which was used in thenext reaction step without further purification. LCMS: (M+H)=190.1.

Step 3. 6-(4-Fluorophenyl)-3-(4-methoxybenzyl)imidazo[1,2-a]pyrimidine

A mixture of 5-(4-fluorophenyl)pyrimidin-2-amine (50 mg, 0.3 mmol),2-chloro-3-(4-methoxyphenyl)propanal (52 mg, 0.26 mmol) in tert-amylalcohol (1.0 mL) in a sealed reaction vial was heated at 130° C. for 3hours. After cooling, the mixture was purified by preparative HPLC toafford the desired product. LCMS: (M+H)=334.0.

Example 5:6-(4-Fluorophenyl)-3-(1-(4-methoxyphenyl)cyclopropyl)imidazo[1,2-a]pyrimidine

This compound was prepared using procedures analogous to those forExample 4. LCMS: (M+H)⁺=360.1.

Example 6:6-(1-(6-(4-Fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl)cyclopropyl)quinoline

This compound was prepared using procedures analogous to those forExample 4. LCMS: (M+H)⁺=381.0.

Example 7:2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step1. 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide

Oxalyl chloride (38.1 mL, 450 mmol) was slowly added to a mixture of4-bromo-3-fluorobenzoic acid (49.3 g, 225 mmol) in dichloromethane (300mL). Subsequently, N,N′-dimethylformamide (1.0 mL) was added and thereaction mixture was stirred at ambient temperature for 2 h. Thereaction mixture was concentrated under reduced pressure andco-evaporated with toluene 3 times. The residue was then dissolved indichloromethane (100 mL). The solution was added dropwise to a mixtureof N,O-dimethylhydroxylamine hydrochloride (30.7 g, 315 mmol) andpotassium carbonate (120 g, 900 mmol) in dichloromethane (300 mL) andwater (300 mL). The reaction mixture was stirred at ambient temperaturefor 2 hours. The organic layer was separated. The aqueous layer wasextracted with dichloromethane (2×50 mL). The combined organic extractswere washed with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give the product. (58.5 g) LCMS:(M+H)=261.9/263.9.

Step 2. 1-(4-Bromo-3-fluorophenyl)ethanone

To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (58.5 g,223 mmol) in tetrahydrofuran (500 mL) was added 3M of methylmagnesiumchloride in THF (125 mL, 380 mmol) at 0° C. The reaction mixture wasstirred for 1 hour at 0° C., and was quenched with cold aqueous ammoniumchloride solution (150 mL). The organic layer was separated andconcentrated under reduced pressure. The residue was redissolved inethyl acetate (100 mL). The aqueous layer was diluted with water (100mL) and was extracted with ethyl acetate (3×50 mL). The organic extractswere combined, washed with brine, and dried over magnesium sulfate.Filtration and concentration under reduced pressure gave the product(48.4 g) which was used in the next reaction step without furtherpurification.

Step 3. (4-Bromo-3-fluorophenyl)(oxo)acetaldehyde and1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone

To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (9.0 g, 41 mmol) indimethyl sulfoxide (40 mL) was added slowly a 48% aqueous solution ofhydrogen bromide. (14 mL) The reaction mixture was stirred at 60° C.overnight and then cooled to ambient temperature, poured into ice water.The precipitate was filtered and washed with water and the solid wasdried under vacuum overnight to obtain 8.1 g of desired product. Theaqueous layer was extracted with ethyl acetate 3 times. The combinedextracts were washed with water, brine, dried, filtered, andconcentrated to give an additional 2.2 g of the desired product. (10.3 gtotal).

Step 4. 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone

To a mixture of 1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone or4-bromo-3-fluorophenyl)(oxo)acetaldehyde (7.0 g, 28 mmol) in toluene (50mL) was added ethyl orthoformate (12 mL, 70 mmol) and p-toluenesulfonicacid (200 mg, 1 mmol). The reaction mixture was refluxed for 4 h. Thereaction mixture was cooled to RT, diluted with ethyl acetate, washedwith aqueous sodium bicarbonate, water, brine, and dried over magnesiumsulfate. Concentration under reduced pressure gave the desired productwhich was used in the next step without further purification.

Step 5. 6-(4-Bromo-3-fluorophenyl)-1,2,4-triazin-3-amine

A mixture of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (15.2 g, 50mmol), aminoguanidine bicarbonate (10.2 g, 75 mmol) and potassiumhydroxide (6.6 g, 100 mmol) in ethanol (200 mL) and water (4 mL) wasrefluxed overnight. The solvent was evaporated under reduced pressureand the residue was washed with acetonitrile and filtered. The filtratewas concentrated under reduced pressure. The residue was dissolved indichloromethane (100 mL), washed with water, brine, and concentratedunder reduced pressure. The residue was dissolved in ethanol (50 mL). Tothe solution was added 0.2N hydrochloric acid (50 mL). The resultantmixture was heated to 110° C. for 8 h, and cooled with an ice-waterbath. The precipitate that formed was collected by filtration and washedwith isopropanol to give the desired product. (5.5 g, 41%) LCMS:(M+H)=286.8/288.8. ¹H-NMR (400 MHz, CDCl₃): 8.60 (s, 1H), 7.79 (dd,J=8.6, 2.0 Hz, 1H), 7.68 (dd, J=8.3, 7.0 Hz, 1H), 7.61 (dd, J=8.3, 2.0Hz, 1H), 5.43 (s, 2H).

Step 6. 3-quinolin-6-ylpropanal

Tris(dibenzylideneacetone)dipalladium (480 mg, 0.52 mmol) andtri-tert-butyl-phosphonium tetrafluoroborate (300 mg, 1.0 mmol) in aflask was evacuated and refilled with nitrogen (2 times). 1,4-dioxane(31 mL) was added followed by consecutive addition of 6-bromoquinoline(7.2 g, 35 mmol), 2-propen-1-ol (4.7 mL, 69 mmol) andN-cyclohexyl-N-methyl-cyclohexanamine (8.9 mL, 42 mmol). The reactionvessel was evacuated and refilled with nitrogen (2 times). The reactionmixture was stirred at 30° C. for 24 h. Diethyl ether (30 mL) was addedto the reaction mixture and then filtered and washed with diethyl ether.The organic extract was concentrated under reduced pressure. The residuewas purified by flash chromatography eluting with ethyl acetate inhexanes (0-50%) to afford the desired product. (˜55%) LCMS: (M+H)=186.0;(M+H₂O+H)⁺=204.0.

Step 7. 2-chloro-3-quinolin-6-ylpropanal

L-Proline (410 mg, 3.5 mmol) was added to a solution of3-quinolin-6-ylpropanal (3.27 g, 17.6 mmol) in chloroform (39 mL) at 0°C. followed by addition of N-chlorosuccinimide (2.48 g, 18.5 mmol) andthe reaction mixture was slowly warmed to ambient temperature andstirred for 1 h, monitoring by LCMS. The solvent was concentrated underreduced pressure and the residue was purified on a silica gel columnwith ethyl acetate in hexane (0-50%) to give the desired product. (95%)LCMS: (M+H+H₂O)=237.9/239.9.

Step 8.6-[2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methyl-quinoline

A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (800 mg,2.97 mmol) and 2-chloro-3-quinolin-6-ylpropanal (784 mg, 3.57 mmol) inisopropyl alcohol (10.0 mL) in a sealed tube was heated at 110° C. for48 h. After the reaction mixture was cooled to ambient temperature, theproduct was precipitated and collected by filtration. The mother liquorwas concentrated and the residue was dissolved in ethyl acetate, washedwith aqueous sodium bicarbonate, water, brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified on a silica gel column with methanol in dichloromethane (0-6%)to give the desired product. (65%) LCMS: (M+H)=434.0/436.0.

Step 9.2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzo-nitrile

Zinc cyanide (131 mg, 1.11 mmol),tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (78.5 mg,0.136 mmol), and N,N,N′,N′-Tetramethylethylenediamine (0.22 mL, 1.4mmol) were added successively to a mixture of6-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]-triazin-7-yl]methylquinoline(480 mg, 1.10 mmol) in N,N-dimethylformamide (8.7 mL) in a microwavetube. The tube was sealed and degassed three times and heated to 160° C.under microwave irradiation for 500 s. Most of the solvent was removedunder reduced pressure and the residue was dissolved in ethyl acetate,washed with aqueous sodium bicarbonate, water and brine, and dried overmagnesium sulfate. Filtration and concentration afforded a residue whichwas purified on a silica gel column with methanol in dichloromethane(0-6%) to give the desired product. (90%) LCMS: (M+H)=381.0.

Step 10.2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid

2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile(750 mg, 2 mmol) in a concentrated solution of hydrochloric acid (5.0mL, 53 mmol) and water (1.0 mL) was stirred at 105° C. overnight. Thesolvent was removed under reduced pressure and the resultant residue waswashed with water and filtered to provide the crude product which wasdirectly used in next reaction step without further purification. LCMS:(M+H)=400.0.

Step 11.2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (0.350 μg, 0.876 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (540mg, 1.0 mmol) in N,N-dimethylformamide (5.0 mL) were stirred at ambienttemperature for 3 min. A solution of 2M methylamine in THF (3.0 mL) wasslowly added at 0° C. followed by triethylamine (0.61 mL, 4.4 mmol) andthe reaction mixture was stirred for 2 h at ambient temperature. Thereaction mixture was concentrated under reduced pressure to afford ayellow solid. Water (1.0 mL) was added and the solid was filtered andwashed with acetonitrile and water. The yellow solid (260 mg) was shownto be the desired product by LCMS as the free base. The solid was thentreated with 1.05 equivalents of hydrochloric acid to form thehydrochloric acid salt. The mother liquor was further purified bypreparative HPLC to give another batch of the product. (˜90%) LCMS:(M+H)=413.0.

Example 8:2-(4-Bromo-3-fluorophenyl)-7-[(4-methoxyphenyl)thio]imidazo[1,2-b][1,2,4]triazine

Step 1. 1-[(2,2-dimethoxyethyl)thio]-4-methoxybenzene

To an ice cooled solution of sodium ethoxide (3.26 g, 48.0 mmol) inethanol (25.0 mL) was slowly added 4-methoxybenzenethiol (6.73 g, 48.0mmol). The reaction mixture was stirred for 15 min.2-Bromo-1,1-dimethoxyethane (5.64 mL, 48.0 mmol) was added, and thereaction mixture was refluxed for 2 h. After the precipitate wasisolated by filtration, the mother liquor was evaporated under reducedpressure. The resultant residue was diluted with diethyl ether (100 mL)and washed with water and brine, dried over sodium sulfate, filtered,and concentrated to give the desired crude product (11.0 g) which wasdirectly used in next step reaction without further purification. ¹H-NMR(400 MHz, CDCl₃): 7.40 (m, 2H), 6.85 (m, 2H), 4.47 (t, J=5.6 Hz, 1H),3.80 (s, 3H), 3.34 (s, 6H), 3.01 (d, J=5.6 Hz, 2H).

Step 2. [(4-methoxyphenyl)thio]acetaldehyde

1-[(2,2-Dimethoxyethyl)thio]-4-methoxybenzene (11.0 g) was dissolved in1% aqueous hydrochloric acid (60 mL) and acetone (30 mL). The reactionmixture was refluxed for 2 h. Acetone was removed under reduced pressureand the residue was neutralized with aqueous sodium bicarbonate andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel with 20% ethylacetate in hexanes to afford the desired product (8.5 g, 97%). ¹H-NMR(400 MHz, CDCl₃): 9.55 (t, J=4.2 Hz, 1H), 7.36 (m, 2H), 6.84 (m, 2H),3.79 (s, 3H), 3.40 (d, J=4.2 Hz, 2H).

Step 3.2-(4-bromo-3-fluorophenyl)-7-[(4-methoxyphenyl)thio]imidazo[1,2-b][1,2,4]triazine

To a cooled (0° C.) reaction mixture of[(4-methoxyphenyl)thio]acetaldehyde (36.4 mg, 0.2 mmol) and D-proline(4.6 mg, 0.04 mmol) in chloroform (1.2 mL) was addedN-chlorosuccinimide. (26.7 mg, 0.2 mmol). The reaction mixture wasstirred at 0° C. for 30 min, then gradually warmed to RT for 2 h. To thereaction mixture was added[6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol).The reaction mixture was stirred for 1 h. The solvent was removed underreduced pressure. The residue was dissolved in isopropanol (2 mL) andheated at 100° C. overnight. After cooling, the reaction mixture wasfiltered and the filtrate was purified by RP-HPLC (pH=10) to afford thedesired product. LCMS: (M+H)⁺=431.0.

Example 9:2-Fluoro-4-(3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidin-6-yl)-N-methylbenzamide

Step 1. 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzamide

A mixture of 4-bromo-2-fluoro-N-methylbenzamide (900 mg, 3.9 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (710mg, 3.2 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol)and potassium carbonate (1.3 g, 9.7 mmol) in toluene (6.0 mL) andethanol (3.0 mL) and water (3.0 mL) was heated at 110° C. for 2 hours.After cooling to RT, the reaction mixture was quenched with water andextracted with diethyl ether. The solid was filtered and washed withwater and diethyl ether to afford the desired product (720 mg).

Step 2.2-fluoro-4-(3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidin-6-yl)-N-methylbenzamide

This compound was prepared using procedures analogous to those forExample 8. LCMS: (M+H)=409.0.

Example 10:2-chloro-4-3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide

This compound was prepared using procedures analogous to those forExample 8. LCMS: (M+H)=425.0/427.0.

Example 11:2-Fluoro-N-methyl-4-[3-(quinolin-6-ylthio)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. 2-fluoro-4-imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide

A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzamide (123mg, 0.5 mmol) and chloroacetaldehyde (0.318 mL, 2.5 mmol) in isopropylalcohol (4 mL) was stirred at 90° C. for 4 h. The solvent was removedunder vacuum and the residue was triturated with ethyl acetate andhexanes. The solid formed was collected and dried under reduced pressureto give the desired product (120 mg, 88.8%). LCMS: (M+H)=271.0.

Step 2.4-(3-bromoimidazo[1,2-a]pyrimidin-6-yl)-2-fluoro-N-methylbenzamide

Bromine (17.4 μL, 0.338 mmol) was added to a mixture of sodium acetate(40.3 mg, 0.491 mmol) and2-fluoro-4-imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide (83.0 mg,0.307 mmol) in acetic acid (2.6 mL) and the reaction mixture was stirredat ambient temperature for 30 min. The solvent was removed under reducedpressure. The residue was dissolved in ethyl acetate and washed withsaturated sodium bicarbonate and brine, dried over sodium sulfate,filtered, and concentrated. The residue was purified by chromatographyon silica gel with ethyl acetate in dichloromethane (0-50%) to affordthe desired product (95 mg, 88.6%). LCMS: (M+H)=348.8/350.9.

Step 3. quinoline-6-thiol

To a solution of 6-bromoquinoline (0.81 g, 3.89 mmol) inN,N-dimethylacetamide (4 mL) was added sodium methyl mercaptide (2.0 g,28.5 mmol). The mixture was heated at 150° C. for 2 h. After cooling,the mixture was diluted with ethyl acetate, and neutralized with aqueous1N hydrochloric acid. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate. The combined organic extractswere washed with water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wasdirectly used in the next step without further purification. (0.50 g,79%) LCMS: (M+H)⁺=161.9.

Step 4.2-fluoro-N-methyl-4-[3-(quinolin-6-ylthio)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (70 μL, 0.4 mmol),tris(dibenzylideneacetone)-dipalladium(0) (4.58 mg, 0.0050 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.79 mg,0.010 mmol) was added successively to a solution of4-(3-bromoimidazo[1,2-a]pyrimidin-6-yl)-2-fluoro-N-methylbenzamide (69.8mg, 0.2 mmol) in 1,4-dioxane (0.42 mL) in a microwave tube. The tube wassealed and degassed three times, and heated to 100° C. overnight. Aftercooling, the reaction mixture was diluted with methanol, and filtered.The filtrate was purified by RP-HPLC (pH 10) to give the desiredproduct. LCMS: (M+H)=430.0.

Example 12:2-chloro-N-methyl-4-[3-(quinolin-6-ylthio)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 11. LCMS: (M+H)=446.0

Example 13: Methyl2-fluoro-4-[7-(quinolin-6-ylthio)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate

Step 1. 6-[(2,2-dimethoxyethyl)thio]quinoline

To a solution of 6-bromoquinoline (0.832 g, 4.0 mmol) inN,N-dimethylacetamide (4.0 mL) was added sodium methyl mercaptide (0.841g, 12.0 mmol). The reaction mixture was heated at 150° C. for 2 h. Aftercooling, 2-bromo-1,1-dimethoxyethane (1.41 mL, 12.0 mol) was then added,and the reaction mixture was diluted with ethanol (5 mL), and heated at80° C. for 1 h. After the precipitated salt was isolated by filtration,the mother liquor was evaporated under reduced pressure. The residue wasdiluted with diethyl ether (50 mL), washed with water, brine, dried oversodium sulfate, filtered, and concentrated. The residue was directlyused in the next reaction step without further purification. LCMS:(M+H)=249.9.

Step 2. (quinolin-6-ylthio)acetaldehyde

6-[(2,2-Dimethoxyethyl)thio]quinoline (1.0 g) was dissolved in aqueous1N hydrochloric acid (6 mL) and acetone (3 mL). The reaction mixture wasrefluxed for 3 h. Acetone was removed under reduced pressure. Theaqueous layer was neutralized with saturated sodium bicarbonate andextracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel with 20% ethyl acetate in hexanes to affordthe desired product. LCMS: (M+H)=204.0; (M+H₂O)=221.9; (M+MeOH)=236.0.

Step 3. 4-acetyl-2-fluorobenzonitrile

N,N,N′,N′-Tetramethylethylenediamine (0.667 mL, 4.42 mmol), zinc cyanide(1.46 g, 12.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (54.05 mg,0.059 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (124.3 mg,0.215 mmol) was added successively to a solution of1-(4-bromo-3-fluorophenyl)ethanone (4.34 g, 20.0 mmol) inN,N-dimethylformamide (15 mL) in a microwave tube. The tube was sealedand degassed three times, and heated to 160° C. under microwaveirradiation with a 240 s hold time, and 300 Watt maximum power input.After cooling, the reaction mixture was filtered through a pad of Celitewith a thin layer of silica gel in the middle using dichloromethane asthe eluant. The combined filtrates were concentrated under reducedpressure. The residue was purified by chromatography on silica gel withethyl acetate in hexanes (0-40%) to give the desired product. (3.20 g,98.1%).

Step 4. 4-acetyl-2-fluorobenzoic acid

A suspension of 4-acetyl-2-fluorobenzonitrile (2.42 g, 14.8 mmol) inaqueous hydrochloric acid (20%, 100 mL) was refluxed (oil bathtemperature: 110° C.) overnight. After cooling, the crystals formed werecollected by filtration and dried to give the desired product (2.16 g).The mother liquor was concentrated under reduced pressure. The residuewas washed with water and filtered to give 300 mg of the desiredproduct. (2.46 g, 91%) LCMS (M+H)=182.9.

Step 5. methyl 4-acetyl-2-fluorobenzoate

4-Acetyl-2-fluorobenzoic acid (46.1 mmol, 0.0461 mol) in dichloromethane(30 mL) was treated with oxalyl chloride (7.8 mL, 92 mmol) andN,N-dimethylformamide (0.2 mL) at 0° C. The reaction mixture was stirredat ambient temperature for 3 h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved in dichloromethane(50 mL, 0.78 mol) and cooled to 0° C. A solution of methanol (4.7 mL)and triethylamine (16 mL, 120 mmol) was added. The reaction mixture wasstirred at ambient temperature for 1 h, washed with water aqueous 1Nhydrochloric acid, and brine. The organic extracts were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography eluting with 20% ethylacetate in hexanes to afford the desired product. (5.64 g, 62.4%).

Step 6. methyl 2-fluoro-4-(oxoacetyl)benzoate

A mixture of methyl 4-acetyl-2-fluorobenzoate (1.6 g, 8.2 mmol) and 8.8Mhydrogen bromide in water (2.8 mL) in dimethyl sulfoxide (20 mL) wasstirred at 60° C. overnight. After cooling, the mixture was poured intoice-water. The reaction mixture was extracted with diethyl ether. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered and concentrated to yield the desired product whichwas used in the next reaction step without further purification. (1.60g, 93.3%).

Step 7. methyl 4-(diethoxyacetyl)-2-fluorobenzoate

A mixture of methyl 2-fluoro-4-(oxoacetyl)benzoate (6.0 g, 0.028 mol),ethyl orthoformate (12.0 mL, 0.071 mol), and p-toluenesulfonic acidmonohydrate (200 mg) in toluene (60 mL) was heated under reflux for 4 h.After cooling, the reaction mixture was concentrated under reducedpressure to give the desired product which was used in the next stepwithout further purification.

Step 8. methyl 2-fluoro-4-[3-(methylthio)-1,2,4-triazin-6-yl]benzoate

Methyl 4-(diethoxyacetyl)-2-fluorobenzoate (3.0 g, 0.01 mol) wasdissolved in ethanol (30 mL). Thiosemicarbazide (1.2 g, 0.013 mol) andp-toluenesulfonic acid monohydrate (100 mg) were added to the reactionmixture. The reaction mixture was heated at 90° C. for 2 h. Aftercooling, the reaction mixture to ambient temperature methyl iodide (3mL, 0.05 mol) was added. The reaction mixture was stirred at RT for 2 h,and then concentrated under reduced pressure. The residue was dissolvedin acetic acid (50 mL), and heated at 60° C. for 2 h. The reactionmixture was concentrated under reduced pressure. The residue was takenup in methanol and the precipitate was collected by filtration and driedunder reduced pressure to give the desired product. (1.2 g, 41%).

Step 9. methyl 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzoate

To a solution of methyl2-fluoro-4-[3-(methylthio)-1,2,4-triazin-6-yl]benzoate (1.2 g, 4.3 mmol)in dichloromethane (90 mL) at 0° C. was added slowly a solution ofm-chloroperbenzoic acid (1.5 g, 6.4 mmol) in dichloromethane. (5.0 ml)The reaction mixture was stirred at 0° C. for 2 h, and quenched withsaturated aqueous sodium thiosulfate. The organic layer was separated,washed with saturated aqueous sodium bicarbonate, water, brine, driedover sodium sulfate, filtered, and concentrated under reduced pressureto yield the desired intermediate. LCMS: 295.9 (M+H).

A mixture of the above intermediate and a 2M solution of ammonia inisopropyl alcohol (20 mL) was stirred at ambient temperature for 2 h.The solid formed was collected by filtration and washed with isopropanolto provide the desired product. (700 mg, 60%) LCMS: 248.9, 267.0.

Step 10. methyl2-fluoro-4-[7-(quinolin-6-ylthio)imidazo[1,2-b[1,2,4]triazin-2-yl]benzoate

To a cooled (0° C.) mixture of (quinolin-6-ylthio)acetaldehyde (40.6 mg,0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) wasadded N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixturewas stirred at 0° C. for 30 min, then gradually warmed to ambienttemperature for 2 h. To the mixture was added methyl4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzoate (24.8 mg, 0.1 mmol). Thereaction mixture was stirred for 1 h. The solvent was removed underreduced pressure. The residue was dissolved in isopropanol (2 mL) andheated to 100° C. overnight. After cooling, the mixture was filtered andthe filtrate was purified by RP-HPLC (pH 10) to afford the desiredproduct. LCMS: (M+H)=432.3.

Example 14:2-(4-Bromo-3-fluorophenyl)-7-(4-methoxyphenoxy)imidazo[1,2-b][1,2,4]triazine

Step 1. (4-methoxyphenoxy)acetaldehyde

1-(2,2-Diethoxyethoxy)-4-methoxybenzene (4.8 g, 20 mmol) was dissolvedin 1% aqueous HCl (30 mL) and acetone (15 mL). The reaction mixture washeated under refluxed for 2 h. Acetone was removed under reducedpressure. The aqueous mixture was neutralized with saturated sodiumbicarbonate, and extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, filtered, and concentrated. The residue wasdried under reduced pressure to afford the desired product which wasused in the next step without further purification. (3.30 g, 99.3%).

Step 2.2-(4-bromo-3-fluorophenyl)-7-(4-methoxyphenoxy)imidazo[1,2-b][1,2,4]triazine

To a cooled (0° C.) mixture of (4-methoxyphenoxy)acetaldehyde (33.2 mg,0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) wasadded N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixturewas stirred at 0° C. for 30 min, then gradually warmed to ambienttemperature for 2 h. To the reaction mixture was added6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol).The reaction mixture was stirred for 1 h and then the solvent wasremoved under reduced pressure. The residue was dissolved in isopropanol(2 mL) and heated to 100° C. overnight. After cooling, the mixture wasfiltered and the filtrate was purified by RP-HPLC (pH 10) to afford thedesired product. LCMS: (M+H)=415.0/416.9.

Example 15:3-(4-Methoxyphenoxy)-6-(4-methyl-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidine

Step 1. 5-(4-methyl-1H-pyrazol-1-yl)pyrimidin-2-amine

A suspension of 4-methyl-1H-pyrazole (0.72 g, 0.0088 mol),5-bromopyrimidin-2-amine (1.3 g, 7.3 mmol), copper(I) iodide (58.2 mg,0.306 mmol), N,N′-dimethylcyclohexane-1,2-diamine (0.193 mL, 1.22 mmol),potassium carbonate (1.77 g, 12.8 mmol) in N,N-dimethylformamide (5.0mL) was irradiated under microwave at 180° C. for 1 h. After cooling,the mixture was purified by chromatography on silica gel with methanolin methylene chloride (0-10%) to afford the desired product. LCMS:(M+H)=176.0.

Step 2.3-(4-methoxyphenoxy)-6-(4-methyl-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidine

This compound was prepared using procedures analogous to those forExample 14. LCMS: (M+H)=322.0.

Example 16:6-(4-Bromophenyl)-3-(4-methoxyphenoxy)imidazo[1,2-a]pyrimidine

Step 1. (2Z)-2-(4-bromophenyl)-3-(dimethylamino)acrylaldehyde

Phosphoryl chloride (55.0 mL, 590 mmol) was added dropwise toN,N-dimethylformamide (80.0 mL) at 0° C. The reaction mixture wasstirred at 0° C. for an additional 30 min after which4-bromophenylacetic acid (43.0 g, 200 mmol) was added portion wise. Theresulting mixture was heated at 70° C. overnight. After cooling, thereaction mixture was added slowly to a mixture of ice and water withexternal cooling. Ice was added intermittently to keep the temperature<10° C. When the quenching was complete, potassium carbonate and icewere added slowly until pH 11 was achieved. Small quantities of ethanolwere added to control frothing. To the alkaline mixture was addedtoluene (120 mL), and the reaction mixture was refluxed for 1.5 hoursand cooled to ambient temperature. The aqueous layer was extracted withtoluene (2×50 mL). The combined organic extracts were washed with water,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was recrystallized from dichloromethane/hexanes togive the desired product. (26.5 g, 52%) LCMS: (M+H)=281.0/283.0.

Step 2. 5-(4-bromophenyl)pyrimidin-2-amine

A mixture of (Z)-2-(4-bromophenyl)-3-(dimethylamino)acrylaldehyde (1.27g, 5 mmol), guanidine hydrochloride (0.525 g, 5.5 mmol) and potassiumcarbonate (1.38 g, 10 mmol) in ethanol (10 mL) was heated at 80° C.overnight. After cooling, the reaction mixture was filtered, washed withmethanol and water, and dried under high vacuum to give the desiredproduct (1.2 g, 96%). LCMS: (M+H)=249.9/251.9.

Step 3. 6-(4-bromophenyl)-3-(4-methoxyphenoxy) imidazo[1,2-a]pyrimidine

This compound was prepared using procedures analogous to those forExample 14. LCMS: (M+H)=395.9/397.9.

Example 17:2-chloro-N-methyl-4-[3-(quinolin-6-yloxy)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. 6-(2,2-dimethoxyethoxy)quinoline

To a cooled (0° C.) solution of quinolin-6-ol (5.81 g, 40 mmol) inN,N-dimethylformamide (30 mL) was slowly added a 1M solution of sodiumhexamethyldisilazane in THF (40 mL, 40 mmol). The mixture was stirredfor 15 min after which 2-bromo-1,1-dimethoxyethane (5.18 mL, 44 mmol)was added. The reaction mixture was then refluxed conditions for 6 h.The solvent was evaporated under reduced pressure. The residue wasdiluted with diethyl ether (100 mL) and washed with water, brine, driedover sodium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography eluting with ethyl acetate in hexanes.(0-50%) to give the desired product. (9 g, 96%) LCMS: (M+H)⁺=233.9.

Step 2. 2-(quinolin-6-yloxy)acetaldehyde

6-(2,2-dimethoxyethoxy)quinoline (9.0 g) was dissolved in aqueous 1Nhydrochloric acid (60 mL) and acetone (30 mL). The reaction mixture washeated under reflux for 3 h. Acetone was removed under reduced pressure.To the residue was added ethyl acetate, and the solution was neutralizedwith aqueous 1N NaOH. The organic layer was washed with brine, driedover sodium sulfate, filtered, and concentrated to afford the desiredproduct which was used in the next step without further purification.(4.8 g) LCMS: (M+H₂O)=205.9, and (M+MeOH)=219.9.

Step 3. 2-chloro-N-methyl-4-[3-(quinolin-6-yloxy)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 14. LCMS: (M+H)=430.0/432.0

Example 18:2-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. quinolin-6-ylacetonitrile

To a mixture of(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 12mmol), tris(dibenzylideneacetone)dipalladium(0) (10 g, 12 mmol),6-bromoquinoline (120 g, 577 mmol) in N,N-dimethylformamide (360 mL) ina 3-neck round bottom flask with stirring under positive nitrogenpressure was added (trimethylsilyl)acetonitrile (98.7 mL, 721 mmol),followed by zinc difluoride (42 g, 400 mmol). The flask was sealed underan atmosphere of nitrogen. The reaction mixture was stirred at 105° C.for 20 h. After cooling the solution to RT, the reaction mixture wasquenched with an aqueous ammonia solution and extracted with ethylacetate (3×500 mL). The combined organic extracts were washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified under flash chromatographyeluting with ethyl acetate in hexanes (0-65%) to afford the desiredproduct. (70 g, 72.1%) LCMS: (M+H)=168.9.

Step 2. 1-quinolin-6-ylcyclopropanecarbonitrile

60 mL of 50% aqueous sodium hydroxide was added to a mixture of1-bromo-2-chloroethane (22.0 mL, 265 mmol), quinolin-6-ylacetonitrile(16.0 g, 66.6 mmol), and benzyltriethylammonium chloride (990 mg, 4.3mmol) at 50° C. The reaction mixture was stirred at 50° C. for 3 h.After cooling to RT, the reaction mixture was poured into 100 mL water,and extracted with dichloromethane (3×100 mL). The combined organicextracts were dried over sodium sulfate, filtered through a pad ofsilica gel eluting with 20% ethyl acetate in dichloromethane. Thefiltrate was concentrated to give the desired product which was used inthe next step without further purification. (12.4 g, 96%).

Step 3. 1-quinolin-6-ylcyclopropanecarbaldehyde

Diisobutylaluminum hydride (1M in THF, 96 mL, 96 mmol) was added to asolution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 63.9 mmol)in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. Thereaction mixture was allowed to warm to −5 to 0° C., and stirred at thattemperature for 3 h. The reaction mixture was cooled to −60° C.Isopropyl alcohol (10 mL) was carefully added dropwise. After stirringfor 30 min, the reaction mixture was warmed to −5 to 0° C. The reactionmixture was diluted with ethyl acetate, quenched with water andextracted with ethyl acetate. The combined organic extracts were washedwith water, brine, dried over sodium sulfate, filtered through a pad ofsilica gel eluting with 40% ethyl acetate in hexanes. The filtrate wasconcentrated to yield the desired product. (12 g, 95.1%).

Step 4. 6-1-[(E)-2-methoxyvinyl]cyclopropylquinoline

To a suspension of chloro(methoxymethyl)triphenylphosphorane (3.5 g, 10mmol) in tetrahydrofuran (10 mL) at −10° C. was added dropwise asolution of 1.0 M potassium tert-butoxide in tetrahydrofuran (10 mL).After the reaction mixture was stirred at RT for 1 hour, the reactionmixture was cooled to 0° C. and a solution of1-quinolin-6-ylcyclopropanecarbaldehyde (500 mg, 2.5 mmol) in THF (5 mL)was added. The mixture was stirred at ambient temperature for 1 h. Thereaction mixture was filtered through a pad of silica gel eluting withdichloromethane. The solution was concentrated and the residue waspurified by flash chromatography eluting with ethyl acetate in hexanes(0-30% in 17 min) to afford the desired product. (450 mg, 78.8%) LCMS:(M+H)=226.3.

Step 5. (1-quinolin-6-ylcyclopropyl)acetaldehyde

To a solution of 6-1-[(E)-2-methoxyvinyl]cyclopropylquinoline (450 mg,2.0 mmol) in THF (30 mL) was added 3 ml of 10% aqueous HCl solution atambient temperature with stirring. The reaction mixture was stirred atambient temperature for 2 h, and then neutralized with saturated sodiumbicarbonate. The mixture was extracted with ethyl acetate. The organicextract was washed with brine, dried over sodium sulfate, filtered, andconcentrated to yield the desired product which was used in the nextreaction step without further purification. (410 mg, 97.2%) LCMS:(M+H)=212.2; (M+H₂O+H)=230.2.

Step 6. chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde

To a mixture of (1-quinolin-6-ylcyclopropyl)acetaldehyde (410 mg, 1.94mmol), D-proline (45 mg, 0.39 mmol) in dichloromethane (10 mL) cooled(0° C.) was added N-chlorosuccinimide (311 mg, 2.33 mmol) with stirring.The reaction mixture was stirred at 0° C. for 1 h, then gradually warmedto RT. The reaction mixture was quenched with water, extracted withdichloromethane. The combined organic extracts were concentrated and theresidue purified by flash chromatography eluting with ethyl acetate inhexanes (0-25% in 18 min) to afford the desired product. (320 mg, 67.1%)LCMS: (M+H)=246.2; (M+H₂O+H)=264.2.

Step 7. 2-fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzamide (0.72g, 2.9 mmol) and1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione(1.0 g, 2.9 mmol) in ethanol (20 mL) was stirred at 105° C. overnight.After cooling, the reaction mixture was purified by RP-HPLC (pH=2) toafford the desired product as the trifluoroacetic acid salt. (1.0 g,43.9%) LCMS: (M+H)=438.0.

Example 19:6-(4-bromophenyl)-3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidine

This compound was prepared using procedures analogous to those forExample 8. LCMS: (M+H)=412.0/414.0; ¹H-NMR (400 MHz, CDCl₃): 8.83 (d,J=2.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.65 (m, 2H), 7.39(m, 2H), 7.14 (m, 2H), 6.80 (m, 2H), 3.75 (s, 3H).

Example 20:2-(4-fluorophenyl)-7-[(4-methoxyphenyl)thio]imidazo[1,2-b][1,2,4]triazine

This compound was prepared using procedures analogous to those forExample 8. LCMS: (M+H)=353.0; ¹H-NMR (400 MHz, CDCl₃): 8.88 (s, 1H),8.16 (s, 1H), 7.96-8.01 (m, 4H), 7.45 (m, 2H), 6.82 (m, 2H), 3.76 (s,3H).

Example 21:6-(1-{6-[3-Fluoro-4-(1-methyl-2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

Step1. 4-(2-aminopyrimidin-5-yl)-2-fluorophenol

A mixture of 5-bromopyrimidin-2-amine (3.3 g, 19 mmol),(3-fluoro-4-hydroxyphenyl)moronic acid (2.7 g, 17 mmol),tetrakis(triphenylphosphine)palladium (0.6 g, 0.5 mmol), sodiumcarbonate (18.3 g, 172 mmol) in ethanol (15 mL), water (5 mL) andtoluene (15 mL) was heated at 120° C. for 3 h. The volatiles wereremoved under reduced pressure. The residue was diluted with EtOAc,washed with water and brine, dried over MgSO₄, filtered, andconcentrated to obtain the desired product which was directly used inthe next step.

Step 2. tert-butyl2-[4-(2-aminopyrimidin-5-yl)-2-fluorophenoxy]propionate

To a solution of triphenylphosphine (0.315 g, 1.2 mmol) intetrahydrofuran (THF, 5.0 mL) was added diethyl azodicarboxylate (0.19mL, 1.2 mmol) and tert-butyl (S)-2-hydroxypropanoate (292 mg, 2 mmol)followed by 4-(2-aminopyrimidin-5-yl)-2-fluorophenol (0.20 g, 1.0 mmol)at RT (RT) under nitrogen. The mixture was stirred overnight at RT,evaporated and the residue was purified by chromatography on silica gelto afford the desired product (0.24 g, 72%). LCMS: (M+H)=334.1.

Step 3. tert-butyl2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoate

A mixture of tert-butyl2-[4-(2-aminopyrimidin-5-yl)-2-fluorophenoxy]propanoate (0.33 g, 1.0mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.24 g, 1.0mmol) in isopropanol was heated at 100° C. overnight. After cooling toRT, the mixture was purified by RP-HPLC (pH 2.0) to afford the desiredproduct (0.22 g, 42%). LCMS: (M+H)=525.2.

Step 4.2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoicacid

tert-Butyl-2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoate(100 mg, 0.2 mmol) was dissolved in a mixed solvent of methylenechloride (5.0 mL) and trifluoroacetic acid (5.0 mL). The solution wasstirred at RT for 2 h. The volatiles were evaporated under reducedpressure. The residue was co-evaporated with toluene three times, andwas directly used in next step. LCMS: (M+H)=469.1.

Step 5.6-(1-{6-[3-fluoro-4-(1-methyl-2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

To a solution of2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenoxy}propanoicacid (59.1 mg, 0.126 mmol) in N,N-dimethylformamide (1.0 mL) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(56 mg, 0.126 mmol), pyrrolidine (9.0 mg, 0.13 mmol) andN,N-diisopropylethylamine (0.1 mL) at RT. The mixture was stirred at RTfor 3 h, and then purified by RP-HPLC (pH 10) to afford the desiredproduct. LCMS: (M+H)=522.0.

Example 22:6-{1-[6-(1H-Pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

Step 1. 5-(1H-pyrazol-1-yl)pyrimidin-2-amine

A suspension of 1H-pyrazole (0.42 g, 0.0061 mol),5-bromopyrimidin-2-amine (1.3 g, 7.3 mmol), copper(I) iodide (58.2 mg,0.306 mmol), N,N′-dimethylcyclohexane-1,2-diamine (0.193 mL, 1.22 mmol),potassium carbonate (1.77 g, 12.8 mmol) in N,N-dimethylformamide (5.00mL) was irradiated under microwave at 180° C. for 1 h. After cooling,the mixture was purified by chromatography on silica gel with methanolin methylene chloride (0-10%) to afford the desired product. LCMS:(M+H)=162.1.

Step 2.6-{1-[6-(1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

A mixture of 5-(1H-pyrazol-1-yl)pyrimidin-2-amine (0.08 g, 0.5 mmol) andchloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.1 g, 0.5 mmol) inisopropanol (15 mL) was heated at 90° C. overnight. After cooling, themixture was purified by RP-HPLC (pH 10) to afford the desired product.LCMS: (M+H)=353.1.

Example 23:6-{1-[6-(4-Methyl-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared from 4-methyl-1H-pyrazole using proceduresanalogous to those for Example 22. LCMS: (M+H)=367.1.

Example 24:N,N-Dimethyl-1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxamide

Step 1. ethyl1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-3-carboxylate

This compound was prepared from ethyl 1H-pyrazole-3-carboxylate usingprocedures analogous to those for Example 22, Steps 1 and 2. LCMS:(M+H)=425.1.

Step 2.1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylicacid

Ethyl1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylate(0.42 g, 1.0 mmol) was dissolved in methanol (10 mL), and was treatedwith an aqueous solution of lithium hydroxide (0.048 g, 2.0 mmol) inwater (5 mL). The mixture was stirred at 50° C. for 2 h, cooled to RT,neutralized with 1N HCl (2 mL). The volatiles were removed under reducedpressure. The residue was co-evaporated with toluene (3×), and dried toafford the desired product which was directly used in next step. LCMS:(M+H)=397.1.

Step 3.N,N-dimethyl-1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxamide

To a solution of1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylicacid (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(65 mg, 0.15 mmol), dimethylamine (2M in THF, 0.10 mL, 0.2 mmol) andN,N-diisopropylethylamine (0.10 mL). The mixture was stirred at RT for 2h, and purified by RP-HPLC (pH 10) to afford the desired product. LCMS:(M+H)=424.1.

Example 25:N-[1-(4-Methyl-1,3-thiazol-2-yl)ethyl]-1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxamide

This compound was prepared from1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxamideacid using procedure analogous to those for Example 24. LCMS:(M+H)=521.0.

Example 26:N-Cyclohexyl-3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxamide

Step 1. methyl3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylate

A mixture of methyl 2-aminopyrimidine-5-carboxylate (153 mg, 1.0 mmol)and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (270 mg, 1.1 mmol) inisopropyl alcohol (3 mL) was heated at 100° C. for 4 h. After cooling toRT, the mixture was diluted with methanol (3 mL) and subjected topreparative RP-HPLC to afford the two regioisomers: methyl3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylate(Isomer-I, 45 mg, R, =1.763 min.) and methyl3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-7-carboxylate(Isomer-II, 89 mg, R, =1.001 min.). LCMS: (M+H)=345.1.

Step 2.3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylic acid

A mixture of methyl3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylate (14mg, 0.040 mmol, isomer-I from Step 1), 1M lithium hydroxide in water(0.16 mL), and methanol (1.0 mL) was stirred overnight at RT. Themixture was neutralized with 1N HCl (0.16 mL) and concentrated underreduced pressure. The residue was dried to yield the desired productwhich was directly used in next step. LCMS: (M+H)=331.0.

Step 3.N-cyclohexyl-3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxamide

Triethylamine (13.9 μL, 0.1 mmol) was added to a mixture of3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylic acid(8.26 mg, 0.025 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (14.3 mg, 0.0275 mmol) and cyclohexanamine (5.7 μL,0.05 mmol) in N,N-dimethylformamide (0.5 mL) at RT. The mixture wasstirred at RT for 2 h, and diluted with methanol (1.3 mL). The resultingsolution was purified by RP-HPLC to give the desired product. LCMS:(M+H)=412.1.

Example 27:3-(1-Quinolin-6-ylcyclopropyl)-N-(tetrahydrofuran-2-ylmethyl)imidazo[1,2-a]pyrimidine-6-carboxamide

This compound was prepared from3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxylic acidusing procedure analogous to those for Example 26. LCMS: (M+H)=414.1.

Example 28:N-Cyclobutyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. tert-butyl 4-(2-aminopyrimidin-5-yl)benzoate

Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to amixture of 5-bromopyrimidin-2-amine (0.348 g, 2.0 mmol),[4-(tert-butoxycarbonyl)phenyl]boronic acid (0.533 g, 2.4 mmol) andtetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3mL) and toluene (3 mL). The mixture was heated at 120° C. for 3 h. Aftercooling to RT, the mixture was diluted with EtOAc and washed with waterand brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the desired product (470mg, 86.6%) which was directly used in next step. LCMS: (M+H)=272.1.

Step 2. tert-butyl4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate

A mixture of tert-butyl 4-(2-aminopyrimidin-5-yl)benzoate (0.144 g,0.531 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.156 g,0.637 mmol) in isopropyl alcohol (3 mL) was heated at 90° C. overnight.The mixture was adjusted to pH=9 using triethylamine, solvent wasremoved and the residue was purified by chromatography on silica gelusing MeOH in methylene chloride (0-5%) to afford the desired product(125 mg, 50.9%). LCMS: (M+H)=463.1.

Step 3.4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid

tert-Butyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate(0.125 g, 0.27 mmol) was treated with 4M HCl in 1,4-dioxane (1.5 mL) atRT for 3 h. The mixture was decanted. The solid was washed with etherand dried to give the desired product as HCl salt (129 mg, 99.5%) whichwas directly used in next step without further purification. LCMS:(M+H)=407.1.

Step 4.N-cyclobutyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (30.0 μL, 0.172 mmol) was added to a mixtureof 4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride (18.5 mg, 0.0386 mmol), cyclobutanamine (4.12 mg,0.0579 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (20.5 mg, 0.0463 mmol) in N,N-dimethylformamide (1mL). The mixture was stirred at RT for 3 h, and diluted with methanol(0.8 mL). The resulting solution was purified by RP-HPLC (pH 10) to givethe desired product. LCMS: (M+H)=460.1.

Example 29:6-(1-{6-[4-(Azetidin-1-ylcarbonyl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=446.1.

Example 30:N,N-Dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=434.1.

Example 31:4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=490.1.

Example 32:N-(1-Benzylpyrrolidin-3-yl)-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=579.2.

Example 33:N-(1-Pyridin-2-ylpiperidin-4-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=566.2.

Example 34:N-(1-Pyridin-2-ylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=511.1.

Example 35:6-{1-[6-(4-[(3S)-3-Fluoropyrrolidin-1-yl]carbonylphenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=478.1.

Example 36:N-[1-(Methoxymethyl)cyclobutyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=504.1 Example 37:N-(1-Pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. tert-butyl (1-pyridin-2-ylpyrrolidin-3-yl)carbamate

A mixture of 2-fluoropyridine (1.0 g, 10.3 mmol) and tert-butylpyrrolidin-3-ylcarbamate (1.80 g, 9.66 mmol) was heated at 120° C. for 5h. After cooling to RT, the solid formed was treated with ether,filtered, and washed with ether. The solid was collected and dried togive the desired product (2.50 g, 98.2%). LCMS: (M+H)=264.1.

Step 2. 1-(pyridin-2-yl)pyrrolidin-3-amine dihydrochloride

tert-Butyl (1-pyridin-2-ylpyrrolidin-3-yl)carbamate (2.5 g) wasdissolved in methanol (4 mL) and was treated with 4M hydrogen chloridein 1,4-dioxane (8 mL). The mixture was stirred overnight at RT. Thesolvents were evaporated under reduced pressure. The residue was washedwith ether and dried to give the desired product (2.1 g, 92%). LCMS:(M+H)=164.1.

Step 3.N-(1-pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=552.2.

Example 38:6-[1-(6-{4-[(3-Pyridin-2-ylpyrrolidin-1-yl)carbonyl]phenyl}imidazo[1,2-a]pyrimidin-3-yl)cyclopropyl]quinoline

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=537.2.

Example 39:6-{1-[6-(4-[(3S)-3-(Pyridin-2-yloxy)pyrrolidin-1-yl]carbonylphenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

Step 1. (S)-2-(pyrrolidin-3-yloxy)pyridine dihydrochloride

To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate(0.936 g, 5.0 mmol) in N,N-dimethylformamide (5 mL) was added sodiumhydride (0.3 g, 7.5 mmol). The mixture was stirred at RT for 30 minfollowed by addition of 2-fluoropyridine (0.5 g, 5.15 mmol). The mixturewas heated at 80° C. overnight. After cooling to RT, the mixture waspoured into ice-water, and extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give the crude product. LCMS: (M+56)=209.1.

The above product was treated with 4M of hydrogen chloride in1,4-dioxane (4.0 mL) and stirred at RT for 1 h. Ether (10 mL) was addedand the solvent was decanted. The solid was washed with ether and driedto give the desired product (1.07 g, 90.2%).

Step 2.6-{1-[6-(4-[(3S)-3-(pyridin-2-yloxy)pyrrolidin-1-yl]carbonylphenyl)imidazo[,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=553.2.

Example 40:N-[2-(Pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. tert-butyl [2-(pyridin-2-yloxy)ethyl]carbamate

Diethyl azodicarboxylate (630 μL, 4.00 mmol) was added to a mixture of2-hydroxypyridine (0.380 g, 4.0 mmol), tert-butyl(2-hydroxyethyl)carbamate (0.322 g, 2.0 mmol) and triphenylphosphine(1.05 g, 4.0 mmol) in THF (6.0 mL). The mixture was stirred overnight atRT, and concentrated. The residue was chromatographed on silica gel withEtOAc in hexanes to give the product (0.353 g, 74.1%). LCMS:(M+H)=239.2.

Step 2. 2-(pyridin-2-yloxy)ethanamine dihydrochloride

tert-Butyl 2-(pyridin-2-yloxy)ethylcarbamate (0.353 g) was treated with4M of hydrogen chloride in 1,4-dioxane (0.6 mL) at RT for 1 h. Thesolvent was evaporated under reduced pressure. The residue was washedwith ether, and dried to give the desired product (0.30 g, 96.8%).

Step 3.N-[2-(pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=527.1

Example 41:N-[1-Methyl-2-(pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from tert-butyl (2-hydroxypropyl)carbamateusing procedures analogous to those for Example 40. LCMS: (M+H)=541.1.

Example 42:N-(2-Phenoxyethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=526.2.

Example 43:N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1.(2S)-3,3-dimethyl-2-({4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoyl}amino)butanoicacid dihydrochloride

Triethylamine (230 μL) was added to a mixture of4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride (162 mg, 0.339 mmol), tert-butyl(2S)-2-amino-3,3-dimethylbutanoate hydrochloride (75.8 mg, 0.339 mmol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (165 mg, 0.373 mmol) in methylene chloride (10 mL).The mixture was stirred at RT for 3 h, washed with NaHCO₃ (7.5%) andbrine, dried over Na₂SO₄, filtered, and concentrated. The residue [LCMS:(M+H)=576.2] was treated with HCl in 1,4-dioxane (4M, 1.0 mL) at RT for3 h. The solvent was evaporated. The residue was washed with ether anddried to give the desired product.

Step 2.N-(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (30.0 μL, 0.172 mmol) was added to a mixtureof(2S)-3,3-dimethyl-2-(4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)butanoicacid dihydrochloride (15.4 mg, 0.0260 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(12.6 mg, 0.0286 mmol) and methylamine (2M in THF, 0.020 mL) inN,N-dimethylformamide (1.0 mL). The mixture was stirred at RT for 3 h,and diluted with methanol (0.8 mL). The resulting solution was purifiedby RP-HPLC (pH=10) to give the desired product. LCMS: (M+H)=533.2.

Example 44:N-(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from(2S)-3,3-dimethyl-2-(4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)butanoicacid dihydrochloride using procedures analogous to those for Example 43.LCMS: (M+H)=547.2.

Example 45:N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from(2S)-3,3-dimethyl-2-(4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)butanoicacid dihydrochloride using procedures analogous to those for Example 43.LCMS: (M+H)=559.2.

Example 46:N-Cyclopropyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. tert-butyl 3-(2-aminopyrimidin-5-yl)benzoate

Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to amixture of 5-bromopyrimidin-2-amine (0.348 g, 2.0 mmol),[3-(tert-butoxycarbonyl)phenyl]boronic acid (0.533 g, 2.4 mmol) andtetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3.0mL) and toluene (3.0 mL). The resulting mixture was heated at 120° C.for 3 h. The mixture was diluted with EtOAc and washed with water andbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was treated withmethanol. The precipitate was filtered and dried to give the product(399 mg, 73.5%). 272.1.

Step 2.3-[3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid

A mixture of tert-butyl 3-(2-aminopyrimidin-5-yl)benzoate (167 mg, 0.616mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (151 mg, 0.616mmol) in isopropyl alcohol (3 mL, 40 mmol) was heated at 90° C.overnight. The solvent was evaporated and the residue was treated with50% TFA in methylene chloride (2.0 mL) at RT for 2 h. The solvents wereevaporated and the residue was washed with ether, and dried to give thedesired product as a TFA salt (0.36 g) which was directly used in nextstep without further purification. LCMS: (M+H)+=407.1.

Step 3.N-cyclopropyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (194 μL, 1.11 mmol) was added to a mixture of3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid TFA salt (126.9 mg, 0.2 mmol), cyclopropylamine (17.1 mg, 0.3 mmol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (97.3 mg, 0.22 mmol) in N,N-dimethylformamide (1.0mL). The mixture was stirred at RT for 3 h, and was diluted withmethanol (0.8 mL). The resulting solution was purified by RP-HPLC(pH=10) to give the desired product. LCMS: (M+H)=446.1.

Example 47:N-(Pyridin-2-ylmethyl)-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid TFA salt using procedures analogous to those for Example 46. LCMS:(M+H)=497.1.

Example 48:N,N-Dimethyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid TFA salt using procedures analogous to those for Example 46. LCMS:(M+H)=434.1.

Example 49:N-Methyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid TFA salt using procedures analogous to those for Example 46. LCMS:(M+H)=420.1.

Example 50:N-[(1S)-1-Methyl-2-(methylamino)-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 43.LCMS: (M+H)=491.1.

Example 51:N-[(1R)-1-Methyl-2-(methylamino)-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 43.LCMS: (M+H)=491.1.

Example 52:(3R)-1-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoyl}pyrrolidine-3-carbonitrile

This compound was prepared from4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride using procedures analogous to those for Example 28.LCMS: (M+H)=485.1.

Example 53: Methyl4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxylate

Step 1. tert-butyl4-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]piperazine-1-carboxylate

Sodium carbonate (1.59 g) in water (6.0 mL) was added to a mixture oftert-butyl4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate(0.205 g, 0.526 mmol), 5-bromopyrimidin-2-amine (0.0940 g, 0.54 mmol)and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in ethanol(6.0 mL) and toluene (6.0 mL). The resulting mixture was heated at 120°C. for 1 h. The mixture was diluted with EtOAc and water. Theprecipitate was collected by filtration to give the desired product (120mg, 63.9%). LCMS: (M+H)=357.1.

Step 2. tert-butyl 4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxylate

A mixture of tert-butyl4-[5-(2-aminopyrimidin-5-yl)pyridin-2-yl]piperazine-1-carboxylate (0.120g, 0.337 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde(0.0827 g, 0.337 mmol) in isopropyl alcohol (2.0 mL) was heated at 100°C. overnight. The mixture was diluted with methanol and purified byRP-HPLC (pH 10.0) to give the desired product (80 mg, 43.4%). LCMS:(M+H)=548.2.

Step 3. 6-{1-[6-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

tert-butyl4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxylate(80.0 mg, 0.146 mmol) in methylene chloride (1.0 mL) was treated withtrifluoroacetic acid (1.0 mL) at RT for 2 h. The volatiles wereevaporated and the residue was co-evaporated with acetonitrile to givethe desired product (125 mg) as a TFA salt which was directly used innext step without further purification. LCMS: (M+H)=448.1.

Step 4. methyl4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxylate

4-Methylmorpholine (19.3 μL, 0.175 mmol) was added to a solution of6-{1-[6-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolineTFA salt (25.0 mg, 0.0292 mmol) in acetonitrile (0.8 mL), followed byaddition of methyl chloroformate (3.39 μL, 0.0438 mmol). The mixture wasstirred at RT for 30 min, and was diluted with methanol (1.0 mL). Theresulting solution was purified by RP-HPLC (pH=10) to give the desiredproduct. LCMS: (M+H)=506.1.

Example 54:6-[1-(6-{6-[4-(Methylsulfonyl)piperazin-1-yl]pyridin-3-yl}imidazo[1,2-a]pyrimidin-3-yl)cyclopropyl]quinoline

This compound was prepared from6-{1-[6-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolineTFA salt using procedures analogous to those for Example 53. LCMS:(M+H)=526.1.

Example 55:N,N-Dimethyl-4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxamide

This compound was prepared from6-{1-[6-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolineTFA salt using procedures analogous to those for Example 53. LCMS:(M+H)=519.2.

Example 56:N-(1S)-1-[(Dimethylamino)carbonyl]-2-methylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. tert-butyl(1S)-1-[(dimethylamino)carbonyl]-2-methylpropylcarbamate

N,N-Diisopropylethylamine (1.0 mL, 5.74 mmol) was added to a mixture of(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (0.217 g, 1.0mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.211 g, 1.1 mmol) and dimethylamine in THF (2M, 1.0 mL) in methylenechloride (10 mL). The mixture was stirred overnight at RT. The mixturewas washed with water, saturated NaHCO₃ solution, brine, dried overNa₂SO₄, filtered, and concentrated. The residue was chromatographed onsilica gel to give the desired product (131 mg, 53.6%).

Step 2. (2S)-2-amino-N,N, 3-trimethylbutanamide hydrochloride

tert-Butyl (1S)-1-[(dimethylamino)carbonyl]-2-methylpropylcarbamate (131mg) was treated with 4M of hydrogen chloride in 1,4-dioxane (1.0 mL) atRT for 2 h. The solvent was evaporated under reduced pressure. Theresidue was dried to give the desired product (96 mg).

Step 3.N-(1S)-1-[(dimethylamino)carbonyl]-2-methylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (40.0 μL, 0.23 mmol) was added to a mixture of4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid dihydrochloride (21 mg, 0.044 mmol),(2S)-2-amino-N,N,3-trimethylbutanamide hydrochloride (11.9 mg, 0.0657mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (23.2 mg, 0.0526 mmol) in N,N-dimethylformamide (1.0mL). The mixture was stirred at RT for 3 h, and was diluted withmethanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH10) to give the desired product. LCMS: (M+H)=533.2.

Example 57:N-1-[(Dimethylamino)carbonyl]cyclobutyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from1-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid using proceduresanalogous to those for Example 56. LCMS: (M+H)=531.2.

Example 58:N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide

Step 1. 5-(2-aminopyrimidin-5-yl)picolinic acid

Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to amixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.442μg, 2.0 mmol), 5-bromopyridine-2-carboxylic acid methyl ester (0.518 g,2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol)in ethanol (3.0 mL) and toluene (3.0 mL). The resulting mixture washeated at 120° C. for 3 h. The organic solvents were removed underreduced pressure. The residue was diluted with water, and adjusted with1N HCl to pH=4. The precipitates were collected by filtration, washedwith water and EtOAc, and dried to give the desired product (0.25 g,58%). LCMS: (M+H)=217.0.

Step 2. tert-butyl(2S)-2-([5-(2-aminopyrimidin-5-yl)pyridin-2-yl]carbonylamino)-3,3-dimethylbutanoate

N,N-Diisopropylethylamine (1.13 mL, 6.48 mmol) was added to a mixture oftert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (0.250 g,1.12 mmol), and 5-(2-aminopyrimidin-5-yl)pyridine-2-carboxylic acid(0.242 g, 1.12 mmol) in N,N-dimethylformamide (10 mL). The mixture wasstirred at RT for 3 h, and filtered. The filtrate was diluted withmethanol (10 mL). The resulting solution was purified by RP-HPLC (pH 10)to give the desired product (182 mg, 42.3%). LCMS: (M+H)=386.2.

Step 3.(2S)-3,3-dimethyl-2-[({5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}carbonyl)amino]butanoicacid

A mixture of tert-butyl(2S)-2-([5-(2-aminopyrimidin-5-yl)pyridin-2-yl]carbonylamino)-3,3-dimethylbutanoate(0.182 g, 0.472 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde(0.128 g, 0.519 mmol) in isopropyl alcohol (2 mL) was heated at 90° C.overnight. The mixture was adjusted to pH 9 by adding triethylamine, andthe solvent was removed. The residue was purified by chromatography onsilica gel using MeOH in methylene chloride (0-5%) to give thetert-butyl ester (0.21 g, 77.1%). LCMS: (M+H)=577.2.

The above tert-butyl ester (0.21 g) was treated with 4M of hydrogenchloride in 1,4-dioxane (1.0 mL) at RT for 3 h. The ether (3 mL) wasadded. The solvent was decanted. The residue was washed with ether, anddried to give the desired product as a HCl salt (0.229 g). LCMS:(M+H)=521.3.

Step 4.N-[(1S)-1-(azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide

N,N-Diisopropylethylamine (30 μL, 0.172 mmol) was added to a mixture of(2S)-3,3-dimethyl-2-[(5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ylcarbonyl)amino]butanoicacid trihydrochloride (16.4 mg, 0.026 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(12.6 mg, 0.0286 mmol) and azetidine hydrochloride (3.65 mg, 0.039 mmol)in N,N-dimethylformamide (1.0 mL). The mixture was stirred at RT for 3h, and was diluted with methanol (0.8 mL). The resulting solution waspurified by RP-HPLC (pH 10) to give the desired product. LCMS:(M+H)=560.2.

Example 59:N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide

This compound was prepared from(2S)-3,3-dimethyl-2-[(5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ylcarbonyl)amino]butanoicacid trihydrochloride using procedures analogous to those for Example58. LCMS: (M+H)=534.2.

Example 60:N-(1S)-1-[(Cyclopropylamino)carbonyl]-2,2-dimethylpropyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide

This compound was prepared from(2S)-3,3-dimethyl-2-[(5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ylcarbonyl)amino]butanoicacid trihydrochloride using procedures analogous to those for Example58. LCMS: (M+H)=560.2.

Example 61:N-[(1S)-2-(Dimethylamino)-1-methyl-2-oxoethyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide

This compound was prepared from(2S)-3,3-dimethyl-2-[(5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ylcarbonyl)amino]butanoicacid trihydrochloride using procedures analogous to those for Example58. LCMS: (M+H)=506.2.

Example 62:N-[(1R)-2-(Dimethylamino)-1-methyl-2-oxoethyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide

This compound was prepared from(2S)-3,3-dimethyl-2-[(5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ylcarbonyl)amino]butanoicacid trihydrochloride using procedures analogous to those for Example58. LCMS: (M+H)=506.1.

Example 63:6-(1-{6-[4-(2-Oxo-2-pyrrolidin-1-ylethoxy)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

Step 1. 1-[(4-bromophenoxy)acetyl]pyrrolidine

Oxalyl chloride (0.5 mL, 5.9 mmol) was added to a suspension of(4-bromophenoxy)acetic acid (0.462 g, 2.0 mmol) in methylene chloride(10 mL) and 2 drops of N,N-dimethylformamide. The mixture was stirred atRT for 2 h. The solvent was evaporated under reduced pressure. Theresidue was diluted with methylene chloride (10 mL), cooled withice-water bath, and 1M of sodium hydroxide aqueous solution (3.0 mL) wasadded. To the mixture was added pyrrolidine (167 μL, 2.0 mmol). Themixture was stirred and allowed to warm to RT. The organic layer wasseparated, washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was directly used in next step without furtherpurification (550 mg, 96.7%). LCMS: (M+H)=286.0/284.0

Step 2. 5-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-2-amine

Sodium carbonate (0.318 g, 3.0 mmol) in water (2.0 mL) was added to amixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.221μg, 1.0 mmol), 1-[(4-bromophenoxy)acetyl]pyrrolidine (0.341 g, 1.2 mmol)and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) in ethanol(1.5 mL) and toluene (1.5 mL). The resulting mixture was heated at 120°C. for 3 h. The mixture was diluted with EtOAc and washed with water andbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue (0.29 g) was directlyused in next step without further purification. LCMS: (M+H)=299.1.

Step 3.6-(1-{6-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

A mixture of5-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-2-amine (23.9 mg,0.08 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (19.6 mg,0.08 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. overnight.The mixture was diluted with methanol, and purified by RP-HPLC (pH 10)to give the desired product. LCMS: (M+H)=490.1.

Example 64:1-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarbonitrile

This compound was prepared from1-(4-bromophenyl)cyclopropanecarbonitrile using procedures analogous tothose for Example 63, Steps 2 and 3. LCMS: (M+H)=428.1.

Example 65:N,N-Dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzenesulfonamide

Sodium carbonate (79.5 mg) in water (0.5 mL) was added to a mixture ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(93.4 mg, 0.3 mmol), 5-bromopyrimidin-2-amine (43.5 mg, 0.25 mmol) andtetrakis(triphenylphosphine)palladium (8.7 mg, 0.0075 mmol) in ethanol(1.0 mL) and toluene (1.0 mL). The resulting mixture was heated at 120°C. for 2 h. The mixture was diluted with water, filtered, and washedwith water. The solid was collected and dried.Chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (45.0 mg, 0.183 mmol) inisopropanol (1.0 mL) was added to the above solid. The mixture washeated at 90° C. overnight. After cooling to RT, the mixture was dilutedwith methanol, and purified by RP-HPLC (pH 10) to give the desiredproduct. LCMS: (M+H)=470.1.

Example 66: Methyl2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzylcarbamate

Step 1. methyl (4-bromo-2-fluorobenzyl)carbamate

Methyl chloroformate (85.0 μL, 1.1 mmol) was added to a solution of1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) andtriethylamine (148.1 μL, 1.1 mmol) in methylene chloride (5 mL) at 0° C.After 10 min, the ice-water bath was removed. The mixture was stirred atRT for 1 h, washed with water, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue (220 mg, 83.9%) was directly used in next step without furtherpurification. LCMS: (M+H)=263.9/261.8.

Step 2. methyl2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzylcarbamate

This compound was prepared from methyl (4-bromo-2-fluorobenzyl)carbamateusing procedures analogous to those for Example 63, Steps 2 and 3. LCMS:(M+H)=468.1.

Example 67:N′-2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl-N,N-dimethylurea

Step 1. N′-(4-bromo-2-fluorobenzyl)-N,N-dimethylurea

N,N-Dimethylcarbamoyl chloride (101 μL, 1.1 mmol) was added to asolution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol)and triethylamine (148.1 μL, 1.10 mmol) in methylene chloride (5 mL) at0° C., followed by 4-dimethylaminopyridine (0.012 g, 0.1 mmol). After 10min, the ice-water bath was removed and the mixture was stirredovernight at RT. The mixture was washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue (253 mg, 91.9%) was directly used in nextstep without further purification. LCMS: (M+H)=276.9/274.9.

Step 2. N′-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[,2-a]pyrimidin-6-yl]benzyl-N,N-dimethylurea

This compound was prepared fromN′-(4-bromo-2-fluorobenzyl)-N,N-dimethylurea using procedures analogousto those for Example 63, Steps 2 and 3. LCMS: (M+H)=481.1.

Example 68:(3R)-1-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl}pyrrolidin-3-ol

Step 1. (3R)-1-(4-bromo-2-fluorobenzyl)pyrrolidin-3-ol

4-bromo-2-fluorobenzaldehyde (203.0 mg, 1.0 mmol) was mixed with(3R)-pyrrolidin-3-ol (87.1 mg, 1.0 mmol) in 1,2-dichloroethane (10 mL).The mixture was stirred at RT for 5 min, and then was treated withsodium triacetoxyborohydride (318 mg, 1.5 mmol). The mixture was stirredat RT for 2 h, and quenched by adding 1N NaOH. The organic phase wasseparated. The aqueous phase was extracted with methylene chloride. Thecombined organic phases were washed with brine, dried over Na₂SO₄,filtered, and concentrated to give the crude product (252 mg, 91.9%)which was directly used in next step without further purification. LCMS:(M+H)=275.9/273.9.

Step 2.(3R)-1-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl}pyrrolidin-3-ol

This compound was prepared from(3R)-1-(4-bromo-2-fluorobenzyl)pyrrolidin-3-ol using proceduresanalogous to those for Example 63, Step 2 and 3. LCMS: (M+H)=480.1.

Example 69:6-(1-{6-[3-Fluoro-4-(1H-pyrazol-1-ylmethyl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

Step 1. 1-(4-bromo-2-fluorobenzyl)-1H-pyrazole

A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (0.268 g, 1.0mmol), 1H-pyrazole (0.0681 g, 1.0 mmol) and cesium carbonate (0.489 g,1.5 mmol) in N,N-dimethylformamide (1.0 mL) was heated at 90° C. for 3h. After cooling to RT, the mixture was diluted with EtOAc, andfiltered. The filtrate was washed with water and brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue (210 mg, 82.3%) was directly used in next stepwithout further purification. LCMS: (M+H)=256.9/254.9.

Step 2.6-(1-{6-[3-fluoro-4-(1H-pyrazol-1-ylmethyl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

This compound was prepared from 1-(4-bromo-2-fluorobenzyl)-1H-pyrazoleusing procedures analogous to those for Example 63, Step 2 and 3. LCMS:(M+H)=461.0.

Example 70:3-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl}-1,3-oxazolidin-2-one

Step 1. 3-(4-bromo-2-fluorobenzyl)-1,3-oxazolidin-2-one

2-chloroethyl chloridocarbonate (114 μL, 1.1 mmol) was added to amixture of 1-(4-bromo-2-fluorophenyl)methanamine hydrochloride (0.240 g,1.0 mmol) and triethylamine (293 μL, 2.1 mmol). The mixture was stirredat RT for 3 h, and then 1M of potassium tert-butoxide in THF (1.2 mL)was added. The mixture was stirred overnight at RT, diluted withmethylene chloride, washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the desiredproduct which was directly used in next step without furtherpurification. LCMS: (M+H)=275.9/273.9.

Step 2.3-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl}-1,3-oxazolidin-2-one

This compound was prepared from3-(4-bromo-2-fluorobenzyl)-1,3-oxazolidin-2-one using proceduresanalogous to those for Example 63, Step 2 and 3. LCMS: (M+H)=480.0.

Example 71:2-Fluoro-N-methyl-4-[7-(quinoxalin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step 1. 3-quinoxalin-6-ylpropanal

A mixture of 6-bromoquinoxaline (0.40 g, 1.9 mmol), 2-propen-1-ol (0.260mL, 3.8 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.029mmol), tri-tert-butylphosphonium tetrafluoroborate (16 mg, 0.057 mmol)and N-cyclohexyl-N-methyl-cyclohexanamine (0.49 mL, 2.3 mmol) in1,4-dioxane (3.0 mL) was stirred at 40° C. overnight. After cooling toRT, the mixture was filtered, washed with methylene chloride and thefiltrate was concentrated. The crude material was purified bychromatography on silica gel with EtOAc in Hexane (0-40%) to afford thedesired product (195 mg). LCMS: (M+H)=187.3.

Step 2. 2-chloro-3-quinoxalin-6-ylpropanal

To a cooled (0° C.) solution of 3-quinoxalin-6-ylpropanal (0.195 g,0.00105 mol) in chloroform (3 mL) was added D-proline (24 mg, 0.00021mol) followed by N-chlorosuccinimide (147 mg, 0.00110 mol). The mixturewas stirred at 0° C. for 2 h, and then at RT overnight. The mixture wasdiluted with methylene chloride. The solution was washed with water,brine, dried over Na₂SO₄, filtered, and concentrated to yield thedesired product (220 mg, 95%). LCMS: (M+H)=221.3.

Step 3. 6-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoxaline

A mixture of 2-chloro-3-quinoxalin-6-ylpropanal (110 mg, 0.52 mmol), and6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (140 mg, 0.52 mmol) intert-butyl alcohol (4 mL) was stirred at 110° C. overnight. Aftercooling to RT, it was concentrated and purified by chromatography onsilica gel with EtOAc in Hexane (0-40%) to afford the desired product(140 mg, 62%). LCMS: (M+H)=435.2.

Step 4.2-fluoro-4-[7-(quinoxalin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile

A mixture of6-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoxaline(120 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (8.8 mg,0.0096 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(11 mg, 0.019 mmol), zinc cyanide (20.1 mg, 0.171 mmol), andN,N,N′,N′-tetramethylethylenediamine (49.9 μL, 0.331 mmol) inN,N-dimethylformamide (0.2 mL) was irradiated under microwave at 160° C.for 10 min. After cooling to RT, the mixture was concentrated and theresidue was purified by chromatography on silica gel with MeOH inmethylene chloride (0-5%) to afford the desired product (65 mg, 62%).LCMS: (M+H)=382.0.

Step 5.2-fluoro-4-[7-(quinoxalin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid

A mixture of2-fluoro-4-[7-(quinoxalin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile(65 mg, 0.17 mmol) in 10M of hydrogen chloride aqueous solution (0.8 mL)and water (20 μL) was stirred at 105° C. for 3 h. After cooling to RT,the mixture was concentrated to yield the desired product. LCMS:(M+H)=401.3.

Step 6. 2-fluoro-N-methyl-4-[7-(quinoxalin-6-ylmethyl)imidazo[,2-b][1,2,4]triazin-2-yl]benzamide

A mixture of2-fluoro-4-[7-(quinoxalin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (20 mg, 0.05 mmol), methylamine (2M in THF, 37 μL),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(23.2 mg, 0.0524 mmol), and N,N-diisopropylethylamine (26 μL, 0.15 mmol)in 1,4-dioxane (0.5 mL) was stirred at RT for 4 h. The mixture wasdiluted with methanol and purified by RP-HPLC (pH 2) to give the desiredproduct as a TFA salt. LCMS: (M+H)=414.4.

Example 72:6-{1-[6-(4-Chloro-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared from 4-chloro-1H-pyrazole using proceduresanalogous to those for Example 22. LCMS: (M+H)+=387.0.

Example 73:6-{1-[6-(2-Methyl-1,3-thiazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared using procedures analogous to those forExample 63, Step 2 and 3. LCMS: (M+H)=384.0.

Example 74:6-{1-[6-(1,3-Thiazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared using procedures analogous to those forExample 63, Step 2 and 3. LCMS: (M+H)=370.0.

Example 75:3-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1: methyl 3-fluoro-4-[3-(1-quinolin-6ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate

This compound was prepared from 4-bromo-3-fluorobenzoic acid usingprocedures analogous to those for Example 63, Step 2 and 3. LCMS:(M+H)=439.0.

Step 2.3-fluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid

To a solution of methyl3-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate(100 mg, 0.2 mmol) in 5 ml of THF-MeOH—H₂O (3:1:1) was added 2M oflithium hydroxide in water (0.23 mL) at 0° C. under N₂. The solution wasstirred for 10 min at 0° C., and 1.5 h at RT. The reaction solution wasconcentrated to dryness to give the desired product which was directlyused in next step without further purification.

Step 3. 3-fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

3-Fluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid obtained from Step 2 was dissolved in N,N-dimethylformamide (1 mL).To this solution was added methylamine (2M in THF, 0.2 mL),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(110 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.68 mmol).The solution was stirred overnight at RT, diluted with MeOH, andpurified by RP-HPLC (pH 10) to afford the desired compound. LCMS (M+H):m/z=438.0.

Example 76:(3S)-1-{3-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoyl}pyrrolidin-3-ol

This compound was prepared from3-fluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid using procedures analogous to those for Example 75. LCMS:(M+H)=494.1.

Example 77:2,5-Difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2,5-difluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid which was prepared from 4-chloro-2,5-difluorobenzoic acid usingprocedures analogous to those for Example 75. LCMS: (M+H)=456.0.

Example 78:2,5-Difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2,5-difluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid using procedures analogous to those for Example 75. LCMS:(M+H)=442.0.

Example 79:N-Cyclopropyl-2,5-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2,5-difluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid using procedures analogous to those for Example 75. LCMS:(M+H)=482.0.

Example 80:2,5-Difluoro-N-(trans-4-hydroxycyclohexyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2,5-difluoro-4-(3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyrimidin-6-yl)benzoicacid using procedures analogous to those for Example 75. LCMS:(M+H)=540.2.

Example 81:1-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}pyrrolidin-2-one

To a solution of6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline(20 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was added 2-pyrrolidinone (5.7mg, 0.067 mmol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1 mg,0.009 mmol), copper(I) iodide (0.8 mg, 0.004 mmol), and potassiumcarbonate (13 mg, 0.095 mmol). The mixture was irradiated at undermicrowave 150° C. for 1 h. After cooling to RT, the solution waspurified by RP-HPLC (pH=10) to afford the desired compound. LCMS:(M+H)+=464.1.

Example 82:3-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-1,3-oxazolidin-2-one

This compound was prepared from6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolineusing procedures analogous to those for Example 81. LCMS: (M+H)=461.0.

Example 83: Ethyl4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Step 1.6-{1-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

tert-Butyl4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate,which was prepared using a procedure that was analogous to thatdescribed for the synthesis of Example 88 Steps 1-4, was treated withTFA in methylene chloride to afford the desired product. LCMS:(M+H)=436.1.

Step 2. ethyl4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

6-{1-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl})quinoline (4 mg, 0.0092 mmol) was dissolved in N,N-dimethylformamide(0.5 mL) and cooled to 0° C. followed by the addition of ethylchloroformate (1.0 μL, 0.01 mmol) and N,N-diisopropylamine (4.0 μL,0.023 mmol). The solution was allowed to gradually warm to RT over 2 h.The reaction mixture was purified by RP-HPLC (pH 2) to afford thedesired product as a TFA salt. LCMS: (M+H)=508.2.

Example 84:2-(4-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-1H-pyrazol-1-yl)-N,N-dimethylacetamide

Step 1: tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.7mmol) in N,N-dimethylformamide (25 mL) was added tert-butyl2-bromoacetate (1.2 mL, 8.5 mmol) and cesium carbonate (3.8 g, 0.012mol). The suspension was stirred overnight at RT and partitioned withEtOAc and water. The organic phase was washed with brine, dried withMgSO₄, filtered, and concentrated to afford the desired compound whichwas directly used in next step. LCMS: (M+H)=309.4.

Step 2: tert-butyl [4-(4-bromo-2-fluorophenyl)-1H-pyrazol-1-yl]acetate

To a solution of 4-bromo-2-fluoro-1-iodobenzene (380 mg, 1.3 mmol) inTHF (10 mL) was added tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate(390 mg, 1.3 mmol), 2M sodium carbonate in water (2.5 mL) andtetrakis(triphenylphosphine)palladium (40 mg, 0.04 mmol). The solutionwas degassed with N₂, and heated at 80° C. overnight. The mixture wascooled to RT, poured into water, extracted with EtOAc, washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatograph on a silica gel column with EtOAc inHexanes (30%) to afford the desired compound. LCMS: (M+57)=299.0.

Step 3: tert-butyl4-[4-(2-aminopyrimidin-5-yl)-2-fluorophenyl]-1H-pyrazol-1-ylacetate

To a solution of tert-butyl[4-(4-bromo-2-fluorophenyl)-1H-pyrazol-1-yl]acetate (400 mg, 0.001 mol)in 1,4-dioxane (3 mL) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (270mg, 1.2 mmol), potassium phosphate (640 mg, 3.0 mmol) andtetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol). The solutionwas degassed with N₂, and heated at 120° C. for 3 h. The solution wascooled to RT, poured into water, extracted with EtOAc, washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatograph on a silica gel column with EtOAc inHexanes (50%) to afford the desired compound. LCMS: (M+H)=370.1.

Step 4: tert-butyl (4-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl-1H-pyrazol-1-yl)acetate

A mixture of tert-butyl4-[4-(2-aminopyrimidin-5-yl)-2-fluorophenyl]-1H-pyrazol-1-ylacetate (100mg, 0.27 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (67.2mg, 0.273 mmol) in ethanol (2 mL) was stirred at 100° C. overnight. Thesolution was concentrated and the residue was purified by chromatographyon silica gel with EtOAc in CH₂Cl₂ (0-90%) to afford the desiredcompound. LCMS: (M+H)=561.1.

Step 5: 2-(4-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[,2-a]pyrimidin-6-yl]phenyl}-1H-pyrazol-1-yl)-N,N-dimethylacetamide

To a solution of tert-butyl(4-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl-1H-pyrazol-1-yl)acetate(20 mg, 0.04 mmol) in CH₂Cl₂ (2 mL) was added TFA (1 mL) and thesolution was stirred at RT for 2 h. The volatiles were removed underreduced pressure. The residue was dissolved in N,N-dimethylformamide(0.5 mL). treated with 2M dimethylamine in THF (0.036 mL),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(24 mg, 0.054 mmol), and N,N-diisopropylethylamine (19 μL, 0.11 mmol).The solution was stirred at RT for 3 h, and purified by RP-HPLC (pH 10)to afford the desired compound. LCMS: (M+H)=532.0.

Example 85:5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-N-methylpyridine-2-carboxamide

Step 1: 5-(4-bromo-3-fluorophenyl)pyrimidin-2-amine

To a solution of 5-bromopyrimidin-2-amine (2.1 g, 0.012 mol) in1,4-dioxane (30 mL) was added (4-bromo-3-fluorophenyl)boronic acid (2.0g, 0.0091 mol), potassium phosphate (6.4 g, 0.030 mol) andtetrakis(triphenylphosphine)palladium (700 mg, 0.6 mmol), water (5 mL).The solution was degassed with N₂, and heated at 120° C. for 4 h. Themixture was cooled to RT, poured into water, and extracted with EtOAc.The combined organic layers were washed with brine, dried with MgSO₄,filtered, and concentrated. The residue was purified by chromatographyon silica gel with EtOAc in CH₂Cl₂ (0-30%) to afford the desiredcompound. LCMS: (M+H)=267.9.

Step 2:6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

A mixture of 5-(4-bromo-3-fluorophenyl)pyrimidin-2-amine (0.50 g, 1.9mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.463 g, 1.88mol) in ethanol (20 mL) was stirred at 100° C. overnight. The solutionwas concentrated and the residue was purified by chromatography onsilica gel with MeOH in CH₂Cl₂ (0-6%) to afford the desired compound.LCMS: (M+H)=458.9.

Step 3:5-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-N-methylpyridine-2-carboxamide

To a solution of6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline(20 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was addedN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(17 mg, 0.065 mmol), tetrakis(triphenylphosphine)palladium (3 mg, 0.003mmol), and potassium phosphate (28 mg, 0.13 mol). The mixture was heatedat 120° C. overnight. After cooling to RT, the solution was purified byRP-HPLC (pH 2) to afford the desired compound as a TFA salt. LCMS:(M+H)=515.0.

Example 86:5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-N,N-dimethylpyridine-2-carboxamide

This compound was prepared as a TFA salt starting from6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolineusing procedures analogous to those for Example 85. LCMS: (M+H)=529.0.

Example 87:6-(1-{6-[3-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

This compound was prepared as a TFA salt starting from6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolineusing procedures analogous to those for Example 85. LCMS: (M+H)=461.1.

Example 88:6-(1-{6-[1-(Tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

Step 1. tetrahydrofuran-3-yl methanesulfonate

3-Hydroxytetrahydrofuran (83.3 μL, 1.03 mmol) was dissolved in methylenechloride (anhydrous, 2 mL) and cooled to 0° C. followed by the additionof triethylamine (166 μL, 1.2 mmol) and methanesulfonyl chloride (88 μL,1.14 mmol). The reaction mixture was stirred for 16 h while graduallywarming to ambient temperature. The reaction was quenched with water,diluted with methylene chloride (20 mL), and the resulting layers wereseparated. The organic layer was washed with water (2×2 mL) and thecombined aqueous phases were extracted with methylene chloride (2×3 mL).The combined organic phases were washed with brine (2×2 mL), dried overNa₂SO₄, filtered, and concentrated. The crude product was used directlyin the next step.

Step 2.1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Tetrahydrofuran-3-yl methanesulfonate was dissolved inN,N-dimethylformamide (0.5 mL) and added to a pre-stirred solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg,0.52 mmol) and sodium hydride (25 mg, 1.1 mmol) in N,N-dimethylformamide(1 mL). The mixture was heated to 60° C. for 2 d, cooled to RT, andpurified by RP-HPLC to afford the desired product. LCMS: (M+H)=265.1.

Step 3. 5-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine

To a solution of1-(Tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(110 mg, 0.42 mmol) in 1,4-dioxane (3 mL) was added EtOH (1 mL) andwater (0.4 mL). The following reagents were added successively:5-bromopyrimidin-2-amine (75 mg, 0.43 mmol), potassium carbonate (180mg, 1.3 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (20 mg, 0.02 mmol). The vessel was purgedseveral times with N₂ and heated to 100° C. for 4 h. The reactionmixture was filtered through a pad of Celite, concentrated, and purifiedby chromatography on silica gel (40 g column, 0-15% MeOH/methylenechloride) to afford the desired product. LCMS: (M+H)=232.0.

Step 4.6-(1-{6-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

The title compound was prepared as a TFA salt from the condensation of5-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine andchloro(1-quinolin-6-ylcyclopropyl) acetaldehyde using a procedureanalogous to that described for the synthesis of Example 7, Step 8.LCMS: (M+H)=423.1.

Example 89:6-(1-{6-[1-(1-Benzylpyrrolidin-3-yl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

This compound was prepared as a TFA salt using a procedure that wasanalogous to that described for the synthesis of Example 88, Steps 1-4to afford the desired product. LCMS: (M+H)=512.2.

Example 90:6-{1-[6-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

Step 1.6-{1-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared using a procedure analogous to that describedfor the synthesis of Example 88, Steps 3-4 starting from4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole.The trityl group of6-{1-[6-(1-trityl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinolinewas removed upon treatment with ˜1% TFA in acetonitrile and was purifiedby RP-HPLC. LC/MS 353.1 (M+1H)

Step 2.6-{1-[6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

To a solution of6-{1-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl})quinoline (6 mg, 0.017 mmol) in N,N-dimethylformamide (200 μL) was addedpotassium carbonate (4.0 mg, 0.029 mmol) and methyl iodide (3 μL, 0.048mmol). After stirring at RT for 16 h, the reaction mixture was purifiedby RP-HPLC to afford the desired product. LCMS: (M+H)=367.0.

Example 91:N,N-Dimethyl-4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxamide

This compound was prepared using a procedure that was analogous to thatdescribed for the synthesis of Example 83 using methylene chloride as asolvent and N,N-dimethylcarbamoyl chloride as the acylating agent inStep 2 to afford the desired product as a TFA salt. LCMS: (M+H)=507.2.

Example 92:4-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}cyclohexanol

Step1. 4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}cyclohexanone

The crude reaction mixture containing6-(1-{2-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinoline(˜30 mg, 0.07 mmol), prepared using a procedure analogous to thatdescribed for the synthesis of Example 88 starting from1,4-dioxaspiro[4.5]decan-8-ol, was concentrated and treated directlywith AcOH (1 mL), water (100 μL) and heated to 100° C. for 1 h to affordthe desired product, which was purified by RP-HPLC. LCMS: (M+H)=449.2.

Step 2. 4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}cyclohexanol

4-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}cyclohexanone(16 mg, 0.036 mmol) was dissolved in MeOH (1 mL) and cooled to about−20° C. followed by the addition of sodium tetrahydroborate (3.0 mg,0.079 mmol). The reaction mixture was allowed to gradually warm toambient temperature and stirred for 2 h. The reaction mixture waspurified by RP-HPLC (pH 2) to afford the desired product as a TFA salt.LCMS: (M+H)=451.1.

Example 93:{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}acetonitrile

This compound was prepared as a TFA salt using a procedure analogous tothose for Example 88, Steps 2-4. LCMS: (M+H)=392.1.

Example 94:N-Methyl-5-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}pyridine-2-carboxamide

Step 1. 6-(4-bromophenyl)-1,2,4-triazin-3-amine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 7, Steps 3-5 starting from4-bromoacetophenone. LCMS: (M+H₂O+H)=269.0/271.0.

Step 2. 6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline

This compound was prepared from the condensation of6-(4-bromophenyl)-1,2,4-triazin-3-amine andchloro(1-quinolin-6-ylcyclopropyl)acetaldehyde using a procedureanalogous to that described for the synthesis of Example 7, Step 8.LCMS: (M+H)=442.3/444.2.

Step 3.N-methyl-5-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}pyridine-2-carboxamide

To a solution of6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline(10.0 mg, 0.0226 mmol) in 1,4-dioxane (1 mL), EtOH (0.2 mL) and water(0.2 mL) was addedN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide(12 mg, 0.045 mmol), cesium carbonate (15 mg, 0.045 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (1.8 mg, 0.0023 mmol). The reaction vesselwas purged with N₂ and then heated in a sealed tube at 120° C. for 1 h.LCMS and HPLC data indicated that the reaction was complete. The mixturewas purified by RP-HPLC (pH 2) to give the desired product as a TFAsalt. LCMS: (M+H)=498.1.

Example 95:6-{1-[2-(4-Pyrimidin-5-yl-phenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline

This compound was prepared as a TFA salt starting from6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinolineusing procedures analogous to those for Example 94. LCMS: (M+H)=442.1.

Example 96:6-(1-{2-[4-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinoline

Step 1. tert-butyl4-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

This compound was prepared using procedures analogous to those forExample 94. LCMS: (M+H)=545.2.

Step 2.6-(1-{2-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinolinehydrochloride

tert-Butyl4-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl})-3,6-dihydropyridine-1(2H)-carboxylate(36.0 mg, 0.0661 mmol) was dissolved in 4M of hydrogen chloride in1,4-dioxane (5.0 mL) and stirred at RT for 2 h. The volatiles wereremoved under vacuum and the residue was azeotropically washed withacetonitrile. The crude material was used in the next step. LCMS:(M+H)=445.0.

Step 3.6-(1-{2-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinoline

To a solution of6-(1-{2-[4-(1,2,3,6-Tetrahydropyridin-4-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl})cyclopropyl)quinoline hydrochloride (12 mg) in N,N-dimethylformamide (1mL) and acetonitrile (1 mL) was added N,N-diisopropylethylamine (23.0μL, 0.132 mmol; ˜5 equiv.) and acetyl chloride (3.8 μL, 0.053 mmol; ˜2.0equiv.). The resulting solution was stirred at RT for 1 h, quenched withMeOH and purified directly by RP-HPLC (pH 2) to afford the desiredproduct as a TFA salt. LCMS: (M+H)=487.1.

Example 97:6-[1-(2-{4-[1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}imidazo[1,2-b][1,2,4]triazin-7-yl)cyclopropyl]quinoline

This compound was prepared as a TFA salt starting from6-(1-{2-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinolinehydrochloride using procedures analogous to those for Example 96. LCMS:(M+H)=523.2.

Example 98:N,N-Dimethyl-5-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}pyridine-2-carboxamide

This compound was prepared as a TFA salt starting from6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinolineusing procedures analogous to those for Example 94. LCMS: (M+H)=512.3

Example 99:6-(1-{2-[4-(1H-Imidazol-1-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)-quinoline

To a solution of6-{1-[2-(4-bromophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline(15 mg, 0.034 mmol) and 1H-imidazole (2.77 mg, 0.0407 mmol) in1,4-dioxane (0.50 mL) was added(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (0.96 mg, 0.0068 mmol),copper(I) iodide (0.64 mg), and potassium carbonate (9.84 mg). Themixture was refluxed overnight. After cooling to RT, the mixture waspurified by RP-HPLC (pH 2) to afford the desired product as a TFA salt.LCMS: (M+H)=430.4.

Example 100:2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step1.6-{1-[2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline

A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (80.0 mg,0.297 mmol, Example 7, Steps 1-5) andchloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.088 g, 0.36 mmol) inisopropyl alcohol (3 mL) and a drop of water was heated at 110° C. for48 h. The mixture was adjusted to pH 9 with triethylamine. The volatileswere removed under reduced pressure. The residue was purified bychromatography on silica gel with EtOAc in CH₂Cl₂ (0-60%) to afford thedesired product. LCMS: (M+H)=459.9/461.9.

Step 2.2-Fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile

A mixture of6-1-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropylquinoline(0.060 g, 0.13 mmol), potassium hexacyanoferrate(II) trihydrate (0.02 g,0.05 mmol), sodium carbonate (0.016 g, 0.16 mmol) and palladium acetate(0.001 g, 0.006 mmol) in N,N-dimethylacetamide (1.0 mL, 11 mmol) wasstirred at 120° C. for 2 h. The reaction mixture was diluted with EtOAc,washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by chromatography on silica gelwith MeOH in CH₂Cl₂ (0-5%) to afford the desired product. LCMS:(M+H)=407.1.

Step 3. 2-Fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid

2-Fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile(40.0 mg, 0.0984 mmol) in concentrated hydrochloric acid (0.6 mL, 0.006mol) was stirred at 110° C. overnight. The volatiles were removed underreduced pressure. The residue was co-evaporated with toluene, and driedto give the desired product. LCMS: (M+H)=426.0.

Step 4.2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

N,N-Diisopropylethylamine (6.4 μL, 0.037 mmol) was added to a mixture of2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (5.2 mg, 0.012 mmol), trans-4-aminocyclohexanol hydrochloride, andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(8.1 mg, 0.018 mmol) in N,N-dimethylformamide (0.6 mL) at 0° C. and wasstirred overnight at RT. The mixture was diluted with methanol andpurified by RP-HPLC (pH 2) to afford the desired product as a TFA salt.LCMS: (M+H)=523.0.

Example 101:N-Cyclopropyl-2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 100. LCMS:(M+H)=465.0

Example 102:2-Fluoro-N-methyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 100. LCMS:(M+H)=439.1.

Example 103:2-Fluoro-N-[1-(methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 100. LCMS:(M+H)=509.1.

Example 104:2-Fluoro-4-(7-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 100. LCMS:(M+H)=425.1.

Example 105:4-[7-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide

Step 1. Methyl 4-(oxoacetyl)benzoate

To a solution of 4-acetylbenzoic acid methyl ester (25 g, 0.14 mol) indimethyl sulfoxide (300 mL) was added slowly a solution of hydrogenbromide in water (48%, 48 mL) at RT with stirring. The mixture wasstirred at 60° C. overnight. After cooling to RT, it was poured intoice-water. The precipitate was filtered and dried to afford the desiredproduct (15.6 g, 79%).

Step 2. Methyl 4-(diethoxyacetyl)benzoate

A mixture of methyl 4-(oxoacetyl)benzoate (13.5 g, 0.0702 mol), ethylorthoformate (29 mL, 0.18 mol), p-toluenesulfonic acid monohydrate (0.7g) in toluene (150 mL) was refluxed for 2 h. After cooling to RT, thesolvent was removed under reduced pressure. The crude material waschromatographed on silica gel to afford the desired product (15.4 g,82%). LCMS: (M+Na)=289.0.

Step 3. Methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate

A mixture of methyl 4-(diethoxyacetyl)benzoate (15.4 g, 0.0578 mol),semicarbazide hydrochloride (7.1 g, 0.064 mol),N,N-diisopropylethylamine (12 mL, 0.069 mol) in 1,2-dichloroethane (150mL), and methanol (2 mL) was heated at 95° C. for 4 h. To the mixturewas added an additional 0.1 equivalents of semicarbazide hydrochloride.The mixture was stirred at 95° C. for 1 h. After cooling to RT, themixture was diluted with methylene chloride and washed with water,brine, dried over Na₂SO₄, filtered, and concentrated. The residue wasrefluxed with acetic acid (100 mL) and water (1.0 mL) overnight. Themixture was concentrated to yield quantitative crude material which wasdirectly used in the next step.

Step 4. Methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate

A mixture of methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate(13.4 g, 0.0580 mol), phosphoryl chloride (30 mL, 0.3 mol) in chloroform(50 mL) was refluxed (oil-bath temperature about 100° C.) for 2 h. Aftercooling to RT, the mixture was concentrated to remove excess phosphorylchloride. The residue was dissolved in methylene chloride and pouredinto ice-water, and carefully neutralized with K₂CO₃. The organic layerwas separated and the aqueous solution was extracted with methylenechloride. The combined organic phases were dried over Na₂SO₄,concentrated, and further purified by chromatography to afford thedesired product (2.5 g, 17%). LCMS: (M+H)=249.9. ¹H NMR (300 MHz,CDCl₃): δ in ppm, 3.98 (s, 3H), 8.18 (d, 2H), 8.24 (d, 2H), 8.96 (s,1H).

Step5. methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate

A solution of methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate (180 mg,0.721 mmol) and 2M of ammonia in isopropyl alcohol (5 ml, 10 mmol) wasstirred at 25° C. for 3 h. The reaction was diluted with water, and theprecipitate was filtered to give the desired product. LCMS:(M+H₂O+H)=249.0.

Step 6. methyl4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate

A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (160 mg, 0.70mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (200 mg, 0.83mmol) in isopropyl alcohol (6 mL) was heated at 110° C. for 24 h. Themixture was adjusted to pH 9 by adding triethylamine and then thevolatiles were removed under reduced pressure. The residue was purifiedby chromatography on silica gel with EtOAc in CH₂Cl₂ (0-60%) to affordthe desired product (130 mg, 44%). LCMS: (M+H)=421.1.

Step 7.4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid

Lithium hydroxide monohydrate (14 mg, 0.34 mmol) was added to a solutionof methyl4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate(30.0 mg, 0.07 mmol) in THF (0.3 mL), methanol (0.3 mL), and water (0.2mL). The mixture was stirred at RT for 2 h and adjusted to pH 2 withconc. HCl. The volatiles were removed under reduced pressure and theresidue was dried to provide the crude product which was directly usedin the next step without further purification. LCMS: (M+H)=408.1.

Step 8.4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide

N,N-Diisopropylethylamine (13 μL, 0.074 mmol) was added to the mixtureof4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (10.0 mg, 0.0245 mmol), (tetrahydrofuran-2-yl)methanamine (8.0 mg)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (16 mg, 0.037 mmol) in N,N-dimethylformamide (0.5mL) at 0° C. The mixture was stirred at RT for 3 h, and purified byRP-HPLC (pH 2) to afford the desired product as a TFA salt. LCMS:(M+H)=491.1.

Example 106:N-(Pyridin-2-ylmethyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=498.1.

Example 107:N-Cyclopropyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=447.1.

Example 108:N-Cyclobutyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=460.1.

Example 109:N-(1-Pyridin-2-ylcyclopropyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=524.1.

Example 110:N-(2-Hydroxy-1,1-dimethylethyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=479.1.

Example 111:N-[(1S)-1-Benzyl-2-hydroxyethyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=541.1.

Example 112:(3R)-1-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoyl}pyrrolidin-3-ol

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=477.1.

Example 113:4-(7-(1-(Quinolin-6-yl)cyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105. LCMS:(M+H)=491.1.

Example 114:N-Cyclopropyl-N-methyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Sodium hydride (0.54 mg, 0.013 mmol) was added to a solution ofN-cyclopropyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide(3.0 mg, 0.0067 mmol) in THF (0.5 mL) at RT. The mixture was stirred for10 min, and then methyl iodide (1.2 μL, 0.020 mmol) was added. Themixture was stirred for 2 h at RT. LCMS showed the reaction wascomplete. The mixture was diluted with methanol, and purified by RP-HPLC(pH 2) to give the desired product as a TFA salt. LCMS: (M+H)=460.1.

Example 115:N-[1-(Methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step 1. benzyl [1-(hydroxymethyl)cyclopropyl]carbamate

Ethyl chloroformate (0.17 mL, 0.0018 mol) was added to a solution of1-[(benzyloxy)carbonyl]aminocyclopropanecarboxylic acid (0.35 g, 0.0015mol) and triethylamine (0.25 mL, 0.0018 mol) in THF (5.0 mL) at −10° C.The mixture was stirred at RT for 30 min., filtered, and washed withTHF. Sodium tetrahydroborate (0.11 g, 0.0030 mol) in water (1.0 mL) wasadded to the filtrate at 0° C., and stirred at RT for 2 h. The reactionmixture was carefully quenched with 1N HCl, and extracted with EtOAc.The extract was washed with saturated NaHCO₃, brine, dried over MgSO₄,filtered, and concentrated to give the crude product (0.32 g, 97%).LCMS: (M+H)=222.0, (M+Na)=244.0.

Step 2. Benzyl [1-(methoxymethyl)cyclopropyl]carbamate

To a solution of benzyl [1-(hydroxymethyl)cyclopropyl]carbamate (0.32 g,0.0014 mol) in methylene chloride (5.0 mL) was added sequentiallypowdered MS 4 Å, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.77 g,0.0036 mol), and trimethyloxonium tetrafluoroborate (0.43 g, 0.0029 mol)at RT. The mixture was stirred for 5 h, filtered through a pad ofCelite, and washed with EtOAc. The filtrate was washed with 1N HCl,water, brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified by chromatography on silica gel with EtOAc in hexanes(0-30%) to afford the desired product (140 mg, 41%). LCMS: (M+H)=236.1.

Step 3. 1-(Methoxymethyl)cyclopropanamine

To a solution of benzyl [1-(methoxymethyl)cyclopropyl]-carbamate (400.0mg, 1.700 mmol) in methanol (5.0 mL) was added Pd/C (50.0 mg) andstirred under hydrogen (balloon) for 1 h. The mixture was filteredthrough a pad of Celite. The solvent was evaporated under reducedpressure to provide the desired product. LCMS: (M+H)=102.1.

Step 4.N-[1-(methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo-[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105, Step 8. LCMS:(M+H)=491.1.

Example 116:N-[1-(Methoxymethyl)cyclobutyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 115. LCMS:(M+H)=505.3.

Example 117:N-[(1S)-1-(Methoxymethyl)-2-methylpropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 115. LCMS:(M+H)=507.1.

Example 118:N-[4-(Methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step 1. tert-butyl [4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]carbamate

Ethyl chloroformate (0.234 mL, 0.00245 mol) was added to a solution of4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid (0.5g, 2.0 mmol) and triethylamine (0.341 mL, 2.45 mmol) in THF (6.8 mL) at−10° C. The mixture was stirred at RT for 30 min., filtered, and washedwith THF. Sodium tetrahydroborate (0.15 g, 4.1 mmol) in water (1.0 mL)was added to the filtrate at 0° C., and then stirred at RT for 2 h. Thereaction mixture was quenched with saturated NH₄Cl solution, extractedwith EtOAc. The extract was washed with saturated NaHCO₃, brine, driedover MgSO₄, filtered, and concentrated to give the crude product whichwas directly used in next step without further purification. LCMS:(M+Na)=254.1; (M−100+H)=132.1.

Step 2. tert-butyl [4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]carbamate

To a solution of tert-butyl[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]carbamate (0.89 g, 3.8 mmol)in methylene chloride (19.2 mL) was added sequentially powdered MS 4 Å,N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (2.0 g, 9.6 mmol), andtrimethyloxonium tetrafluoroborate (1.1 g, 7.7 mmol) at RT. The mixturewas stirred for 5 h., filtered through a pad of Celite, and washed withEtOAc. The filtrate was washed with aqueous CuSO₄, water, brine, driedover MgSO₄, filtered, and concentrated. The residue was purified bychromatography on silica gel with EtOAc in hexanes (0-30%) to afford thedesired product. LCMS: (M+Na)=268.0

Step 3. 4-(methoxymethyl)tetrahydro-2H-pyran-4-amine hydrochloride

To a solution of tert-butyl[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]carbamate (0.45 g, 0.0018mol) in EtOAc (0.2 mL) was added 4M of hydrogen chloride in 1,4-dioxane(3 mL) and stirred for 2 h. The volatiles were removed under reducedpressure to give the desired compound which was directly used in nextstep without further purification. LCMS: (M+H)=146.2.

Step 4.N-[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105, Step 8. LCMS:(M+H)=535.2.

Example 119:4-[7-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-1,3-thiazol-2-ylbenzamide

N,N-Diisopropylethylamine (6.4 μL, 0.037 mmol) was added to a mixture of4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (5.0 mg, 0.012 mmol), 1,3-thiazol-2-amine (2.3 mg, 0.024 mmol), andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (7.0 mg, 0.018 mmol) in N,N-dimethylformamide (0.6mL) at 0° C. The mixture was stirred for 4 h at RT, and purified byRP-HPLC (pH 2) to afford the desired product as a TFA salt. LCMS:(M+H)=490.0.

Example 120:N-Pyrimidin-4-yl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 119. LCMS:(M+H)=485.1.

Example 121:N-[4-(Methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step 1. (2R)-2-[(tert-butoxycarbonyl)amino]propyl dimethylcarbamate

N,N-Dimethylcarbamoyl chloride (0.12 mL, 0.0013 mol) was added to asolution of tert-butyl [(1R)-2-hydroxy-1-methylethyl]carbamate (0.150 g,0.856 mmol), 4-dimethylaminopyridine (0.02 g, 0.2 mmol) and pyridine(0.14 g, 1.7 mmol) in methylene chloride (3.0 mL). The mixture wasstirred overnight, diluted with EtOAc and washed with 1N HCl, saturatedNaHCO₃ and brine. The organic layers were dried over Na₂SO₄, filtered,and concentrated. The residue was purified by chromatography on silicagel with EtOAc in hexanes (0-30%) to afford the desired product.

Step 2. (2R)-2-aminopropyl dimethylcarbamate hydrochloride

To a solution of (2R)-2-[(tert-Butoxycarbonyl)amino]propyldimethylcarbamate (16.0 mg, 0.0650 mmol) in EtOAc (0.2 mL) was added 4Mof hydrogen chloride in 1,4-dioxane (0.5 mL) and stirred for 1 h. Thevolatiles were removed under reduce pressure to give the desiredcompound. LCMS: (M+H)=147.1.

Step 3.N-[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 105, Step 8. LCMS:(M+H)=536.2

Example 122:N-{(1R)-1-[(Dimethylamino)carbonyl]-2-methylpropyl}-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b]i[1,2,4]triazin-2-yl]benzamide

Step 1. 3-quinolin-6-ylbut-3-en-1-ol

Palladium acetate (100 mg, 0.6 mmol) was added to a solution of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (8.0 g, 31mmol) and 3-bromo-3-buten-1-ol (6.2 g, 41 mmol) in toluene (118 mL) andwater (12 mL) followed by addition of2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (500 mg, 1mmol). The mixture was stirred at 100° C. for 6 h. After cooling to RT,the mixture was diluted with EtOAc, washed with water and brine. Theorganic layers were dried over Na2SO4, filtered, and concentrated. Theresidue was purified by chromatography on silica gel with EtOAc inmethylene chloride (0-50%) to afford the desired product.

Step 2. 3-quinolin-6-ylbutan-1-ol

A mixture of 3-quinolin-6-ylbut-3-en-1-ol (1.0 g, 0.0050 mol), platinumon carbon (5 wt. % supported on activated carbon, wet, Degussa type F101ra/w, 0.20 g) in methanol (15.0 mL) was stirred under hydrogen (with aballoon) at RT for 5 h. The mixture was filtered and the filtrate wasconcentrated to give the desired product (1.0 g, 99%). LCMS:(M+H)=202.1.

Step 3. 3-quinolin-6-ylbutanal

To a solution of 3-quinolin-6-ylbutan-1-ol (0.060 g, 0.30 mmol) inmethylene chloride (3.0 mL) was added2,2,6,6-tetramethyl-1-piperidinyloxy free radical (0.005 g, 0.03 mmol)and iodobenzene diacetate (0.10 g, 0.33 mmol). The reaction was stirredovernight at RT. The mixture was purified by chromatography on silicagel with EtOAc in hexanes (0-40%) to afford the desired product (0.050g, 84%). LCMS: (M+H)=200.0.

Step 4. 2-chloro-3-quinolin-6-ylbutanal

L-Proline (5.8 mg, 0.050 mmol) was added to a solution of3-quinolin-6-ylbutanal (50 mg, 0.25 mmol) in chloroform (0.5 mL) at 0°C. followed by addition of N-chlorosuccinimide (36.9 mg, 0.276 mmol).The mixture was stirred at RT for 2 h, diluted with hexanes andfiltered. The filtrate was concentrated and purified by chromatographyon silica gel with EtOAc in methylene chloride (0-10%) to afford thedesired product (0.048 g, 82%). LCMS: (M+H)=234.1/236.1.

Step 4. Methyl4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate

A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (50 mg, 0.217mmol) and 2-chloro-3-quinolin-6-ylbutanal (61 mg, 0.26 mmol) inisopropyl alcohol (3.0 mL) was heated at 110° C. for 48 h. The mixturewas adjusted to pH 9 by adding triethylamine. The volatiles were removedunder reduced pressure and the residue was purified by chromatography onsilica gel with EtOAc in methylene chloride (0-60%) to afford thedesired product (0.020 g, 22%). LCMS: (M+H)=410.0.

Step 5.4-[7-(1-Quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid

Lithium hydroxide monohydrate (24 mg, 0.57 mmol) was added to a solutionof methyl4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate(47 mg, 0.115 mmol) in THF (0.5 mL) and methanol (0.5 mL) and water (0.2mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction wascomplete. The mixture was adjusted with conc. HCl to pH 2. The volatileswere removed under reduced pressure to provide the crude product whichwas directly used in next step. LCMS: (M+H)=396.1.

Step 6.N-(JR)-1-[(Dimethylamino)carbonyl]-2-methylpropyl-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

N,N-Diisopropylethylamine (13 μL, 0.074 mmol) was added to the mixtureof 4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (9.70 mg, 0.0245 mmol), (2R)-2-amino-N,N,3-trimethylbutanamide (5.3mg, 0.037 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (16 mg, 0.037 mmol) in N,N-dimethylformamide (0.6mL) at 0° C. The mixture was stirred overnight at RT, purified byRP-HPLC (pH 2) to afford the desired compound as a TFA salt. LCMS:(M+H)=522.1.

Example 123:N-Cyclopropyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

N,N-Diisopropylethylamine (6.4 μL, 0.037 mmol) was added to a mixture of4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (4.9 mg, 0.012 mmol, prepared as described in Example 7, Steps1-10), cyclopropylamine (1.4 mg, 0.024 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(9.6 mg, 0.018 mmol) in N,N-dimethylformamide (0.6 mL) at 0′C. Themixture was stirred at RT for 3 h, and purified by RP-HPLC (pH 2) toafford the desired product as a TFA salt. LCMS: (M+H)=439.0.

Example 124:2-Fluoro-N-[1-(methoxymethyl)cyclopropyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid procedures analogous to those for Example 123. LCMS: (M+H)=438.1.

Example 125:2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydro-2H-pyran-4-yl)benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=483.1.

Example 126:(3R)-1-{2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazol[1,2-b][1,2,4]triazin-2-yl]benzoyl}pyrrolidin-3-ol

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=469.1.

Example 127:2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=399.0.

Example 128:2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=497.1.

Example 129:6-{2-[3-Fluoro-4-(1H-imidazol-1-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-ylmethyl}quinoline

To a solution of6-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline(6.5 mg, 0.015 mmol) in 1,4-dioxane (0.5 mL) was added(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (0.42 mg, 0.0030 mmol),copper(I) iodide (0.28 mg, 0.0015 mmol), 1H-imidazole (2.0 mg, 0.030mmol) and potassium carbonate (4.34 mg, 0.0314 mmol). The mixture wasstirred at 100° C. overnight. After cooling to RT, the mixture waspurified by RP-HPLC (pH 2) to give the desired product as a TFA salt.LCMS: (M+H)=422.0

Example 130:3-{2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}-1,3-oxazolidin-2-one

This compound was prepared as a TFA salt starting from6-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinolineusing procedures analogous to those for Example 129. LCMS: (M+H)=441.1.

Example 131:N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step 1. tert-Butyl(2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)-3,3-dimethylbutanoate

N,N-Diisopropylethylamine (160 μL, 0.90 mmol) was added to the mixtureof2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (90.0 mg, 0.225 mmol), tert-butyl(2S)-2-amino-3,3-dimethylbutanoate hydrochloride (63 mg, 0.281 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(150 mg, 0.34 mmol) in N,N-dimethylformamide (2.0 mL) at 0′C. Themixture was stirred overnight at RT and was added to aqueousacetonitrile. The precipitates were filtered, dried to give the desiredproduct (0.093 g, 72%). LCMS: (M+H)=569.5.

Step 2.(2S)-2-(2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)-3,3-dimethylbutanoicacid

Trifluoroacetic acid (1.0 mL, 0.013 mol) was added to a solution oftert-butyl(2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)-3,3-dimethylbutanoate(0.092 g, 0.16 mmol) in methylene chloride (1.0 mL) and stirred at RTfor 2 h. The volatiles were removed under reduced pressure to give thedesired product as a TFA salt. LCMS: (M+H)=513.4.

Step 3.N-(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

N,N-Diisopropylethylamine (20 μL, 0.11 mmol) was added to the mixture of(2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)3,3-dimethylbutanoic acid TFA salt (19.2 mg, 0.0376 mmol), methylamine(2M in THF, 0.2 mL, 0.4 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(25 mg, 0.056 mmol) in N,N-dimethylformamide (0.5 mL) at 0′C. Themixture was stirred at RT for 2 h and purified by RP-HPLC (pH 2) toafford the desired product as a TFA salt. LCMS: (M+H)=526.4.

Example 132:N-(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from(2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)3,3-dimethylbutanoic acid TFA salt using procedures analogous to thosefor Example 131. LCMS: (M+H)=540.4.

Example 133:N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from(2S)-2-(2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoylamino)3,3-dimethylbutanoic acid TFA salt using procedures analogous to thosefor Example 131. LCMS: (M+H)=552.5.

Example 134:N-{(1S)-1-[(Dimethylamino)carbonyl]-3-methylbutyl}-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 131. LCMS:(M+H)=540.4.

Example 135:2-Fluoro-N-{(1R)-3-methyl-1-[(methylamino)carbonyl]butyl}-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 131. LCMS:(M+H)=526.4.

Example 136:N-{(1R)-1-[(Dimethylamino)carbonyl]-3-methylbutyl}-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 131. LCMS:(M+H)=540.4.

Example 137:N-[(1R)-1-(Azetidin-1-ylcarbonyl)-3-methylbutyl]-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 131. LCMS:(M+H)=552.5.

Example 138:3-{4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}propanenitrile

Step 1. 6-bromo-1,2,4-triazin-3-amine

Bromine (3.8 g, 24 mmol) in chloroform (20 mL) was added to a suspensionof 1,2,4-triazin-3-amine (1.92 g, 20.0 mmol) in chloroform (100 mL). Thereaction mixture was stirred at RT for 60 h. The mixture was washed withsaturated NaHCO₃. The organic layer was separated, dried over MgSO₄,filtered, and concentrated. The residue was washed with acetone/hexanes(1/1) and filtered, to give the product (0.78 g, 22%) as a solid. ¹H-NMR(400 MHz, DMSO-d₆): δ in ppm, 8.40 (s, 1H), 7.42 (br, 2H); LCMS:(M+H)=175.2/177.2; (M+H+H₂O)=193.2/195.2.

Step 2. 6-[1-(1-Ethoxyethyl)-1H-pyrazol-4-yl]-1,2,4-triazin-3-amine

Sodium carbonate (510 mg, 4.8 mmol) in water (1 mL) was added to amixture of 6-bromo-1,2,4-triazin-3-amine (0.420 g, 2.40 mmol),1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.766 g, 2.88 mmol), and tetrakis(triphenylphosphine)palladium (100 mg,0.1 mmol) in toluene (7 mL) and ethanol (5 mL). The resulting mixturewas heated at 110° C. for 2 h. The mixture was cooled to RT, dilutedwith water, and extracted with chloroform. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. The residue wastreated with CH₂Cl₂/Et₂O and filtered to give the desired product (0.39g, 69%). LCMS: (M+H)=235.4.

Step 3.6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline

A mixture of 6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-1,2,4-triazin-3-amine(390.0 mg, 1.665 mmol) and 2-chloro-3-quinolin-6-ylpropanal (480 mg, 2.2mmol) in isopropyl alcohol (20 mL) was heated at 110° C. for 2 days.After cooling to RT, 0.2 mL of concentrated HCl was added and stirreduntil completely deprotected. The solid formed was collected byfiltration to give the desired product (0.35 g, 64%). LCMS: (M+H)=328.3.

Step 4.3-{4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}propanenitrile

1,8-Diazabicyclo[5.4.0]undec-7-ene (14 μL, 0.092 mmol) was added to amixture of6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline(10.0 mg, 0.0305 mmol) and 2-propenenitrile (4.0 μL, 0.061 mmol) inacetonitrile (0.2 mL). The mixture was stirred at 60° C. overnight. Themixture was purified by RP-HPLC (pH 2) to give the desired product as aTFA salt. LCMS: (M+H)=381.3.

Example 139:4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-ylacetonitrile

Sodium hydride (2.4 mg, 0.061 mmol) was added to a solution of6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline(10.0 mg, 0.0305 mmol) in N,N-dimethylformamide (0.2 mL) at RT andstirred for 5 min. Bromoacetonitrile (4.1 μL, 0.061 mmol) was then addedand the reaction mixture stirred for 2 h. The reaction mixture was thenpurified by RP-HPLC (pH 2) to give the desired product as a TFA salt.LCMS: (M+H)=367.1.

Example 140:2-{4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}acetamide

Cesium carbonate (40 mg, 0.12 mmol) was added to a solution of6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline(10 mg, 0.0305 mmol) and 2-bromoacetamide (0.0084 g, 0.061 mmol) inN,N-dimethylformamide (0.5 mL). The mixture was stirred at 60° C.overnight, and purified by RP-HPLC (pH 2) to give the desired product asa TFA salt. LCMS: (M+H)=385.3.

Example 141: Methyl4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Step 1. tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.30 g,1.5 mmol) in methylene chloride (4 mL) and triethylamine (0.42 mL, 3.0mmol), cooled with an ice bath, was added methanesulfonyl chloride (0.14mL, 1.8 mmol). The mixture was stirred for 2 h, and partitioned betweenEtOAc and water. The organic layer was washed with 1N HCl, brine, driedover MgSO₄, filtered, and concentrated to give the desired product as asolid (0.41 g, 98%). LCMS: (M+Na)=302.3.

Step 2. tert-Butyl4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-H-pyrazol-1-yl}piperidine-1-carboxylate

A mixture of6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]-methylquinoline(101 mg, 0.308 mmol), tert-butyl4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.17 g, 0.62 mmol) andcesium carbonate (0.30 g, 0.92 mmol) in N,N-dimethylformamide (2 mL) wasstirred at 90° C. overnight. The mixture was purified by RP-HPLC (pH=10)to give the desired product (14 mg). LCMS: (M+H)=511.2.

Step 3.6-[2-(1-Piperidin-4-yl-H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline

Trifluoroacetic Acid (0.5 mL) was added to a solution of tert-butyl4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate(0.014 g, 0.027 mmol) in methylene chloride (0.5 mL) and stirred at RTfor 1 h. The volatiles were removed under reduced pressure and theresidue was purified by RP-HPLC (pH 10) to give the desired product.LCMS: (M+H)=411.1.

Step 4. Methyl4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Methyl chloroformate (4.0 L, 0.051 mmol) was added to a solution of6-[2-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline(7.0 mg, 0.017 mmol) and triethylamine (9.5 L, 0.068 mmol) in methylenechloride (0.5 mL). The mixture was stirred for 1 h, and then purified byRP-HPLC (pH 2) to give the desired product as a TFA salt. LCMS:(M+H)=469.1.

Example 142:2-Fluoro-N-[(1S,2S)-2-hydroxycyclopentyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=483.4.

Example 143:2-Fluoro-N-(2-hydroxyethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=443.2.

Example 144:2-Fluoro-N-[1-(methoxymethyl)cyclobutyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=497.2.

Example 145:2-Fluoro-N-[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=527.4.

Example 146:N-(Cyclopropylmethyl)-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=453.2.

Example 147:2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydro-2H-pyran-4-ylmethyl)benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=497.4.

Example 148:N-[2-(Dimethylamino)ethyl]-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=470.4.

Example 149:2-Fluoro-N-(2-piperidin-1-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=510.2.

Example 150:2-Fluoro-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=510.4.

Example 151:2-Fluoro-N-(pyridin-2-ylmethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=490.4.

Example 152:2-Fluoro-N-(pyridin-3-ylmethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=490.4.

Example 153:2-Fluoro-N-(pyridin-4-ylmethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=490.4.

Example 154:2-Fluoro-N-(2-pyridin-2-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=504.1.

Example 155:2-Fluoro-N-(1-pyridin-3-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=504.3.

Example 156:2-Fluoro-N-(1-pyridin-4-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=504.3.

Example 157:2-Fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=499.3.

Example 158:2-Fluoro-N-[1-(hydroxymethyl)cyclopentyl]-4-[7-(quinolin-6-ylmethyl)imidazo[12-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=497.2.

Example 159:2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Step 1.6-1-[2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]ethylquinoline

A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (100.0 mg,0.3716 mmol, prepared as described for Example 7, Steps 1-5) and2-chloro-3-quinolin-6-ylbutanal (0.10 g, 0.44 mmol, prepared asdescribed for Example 122, Steps 1-4) in isopropyl alcohol (3 mL) washeated at 110° C. for 48 h. The mixture was adjusted to pH 9 by addingtriethylamine. The volatiles were removed under reduced pressure and theresidue was purified by chromatography on silica gel with MeOH inmethylene chloride (0-8%) to afford the desired product (0.10 g, 60%).LCMS: (M+H)=448/450.0.

Step 2.2-Fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile

A mixture of6-1-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]ethylquinoline(0.100 g, 0.223 mmol), potassium hexacyanoferrate(II) trihydrate (30 mg,0.06 mmol), sodium carbonate (0.047 g, 0.45 mmol) and palladium acetate(2 mg, 0.01 mmol) in N,N-dimethylacetamide (1.2 mL) was stirred at 120°C. for 2 h. LCMS showed the reaction was complete. The reaction wasdiluted with EtOAc, washed with water, brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by chromatographyon silica gel with MeOH in methylene chloride (0-10%) to afford thedesired product (0.10 g, 60%). LCMS: (M+H)=395.0.

Step 3.2-Fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid

2-Fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile(50.0 mg, 0.127 mmol) in conc. hydrochloric acid (0.6 mL) was stirred at110° C. overnight. The solvent was removed (w/toluene) to give thedesired product. LCMS: (M+H)=414.0.

Step 4.2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(1-quinolin-6-ylethyl)imidazo[,2-b][1,2,4]triazin-2-yl]benzamide

N,N-Diisopropylethylamine (6.4 μL, 0.037 mmol) was added to the mixtureof2-fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid (5.1 mg, 0.012 mmol), trans-4-aminocyclohexanol hydrochloride (3.7mg, 0.024 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (8.1 mg, 0.018 mmol) in N,N-dimethylformamide (0.6mL) at 0° C. The mixture was stirred at RT for 4 h, and purified byRP-HPLC (pH 2) to give the desired product as a TFA salt. LCMS:(M+H)=511.0.

Example 160:2-Fluoro-N-methyl-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 159. LCMS:(M+H)=427.1.

Example 161:N-Cyclopropyl-2-fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 159. LCMS:(M+H)=453.0.

Example 162:2-Fluoro-N-[1-(methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylethyl)imidazo[12-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from2-fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 159. LCMS:(M+H)=497.0.

Example 163:2-Fluoro-N-(2-methoxy-1-methylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. 4-(2-aminopyrimidin-5-yl)-2-fluorobenzoic acid

A solution of sodium carbonate (1.4 g, 0.014 mol) in water (8 mL) wasadded to a mixture of 4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.5 g,6.8 mmol), and tetrakis(triphenylphosphine)palladium (0.3 g, 0.2 mmol)in toluene (16 mL) and ethanol (8 mL). The resulting mixture was heatedat 120° C. for 15 min. The reaction mixture was washed with ether (3×10mL) to remove impurity. The aqueous layer was adjusted with 1N HCl to pH7.0, and purified by RP-HPLC (pH 10) to afford the desired product.LCMS: (M+H)=234.1.

Step 2.2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid

A mixture of 4-(2-aminopyrimidin-5-yl)-2-fluorobenzoic acid (0.20 g,0.86 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.21 g,0.86 mol) in ethanol (8 mL) was stirred at 100° C. overnight. Thereaction mixture was purified by RP-HPLC to afford the desired product.LCMS: (M+H)=425.0.

Step 3.2-fluoro-N-(2-methoxy-1-methylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

A mixture of2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid (19 mg, 0.045 mmol), 1-methoxypropan-2-amine (8 mg, 0.090 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(40 mg, 0.090 mmol), and N,N-diisopropylethylamine (31 μL, 0.18 mmol) inN,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reactionmixture was purified by RP-HPLC (pH 10) to afford the desired product.LCMS: (M+H)=496.1

Example 164:6-{1-[6-(3-Fluoro-4-[(3S)-3-fluoropyrrolidin-1-yl]carbonylphenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=496.1.

Example 165:2-Fluoro-N-(pyridin-2-ylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=515.1.

Example 166:2-Fluoro-N-(1-pyridin-2-ylcyclopropyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=541.1.

Example 167:2-Fluoro-N-(1-pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=570.2.

Example 168:2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=494.2.

Example 169:2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=508.2.

Example 170:N-Cyclopropyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=464.1.

Example 171:2-Fluoro-N-[(1S)-1-(methoxymethyl)-2-methylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=524.1.

Example 172:2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[12-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=424.0.

Example 173:2-Fluoro-N-methyl-N-2-[methyl(pyridin-2-yl)amino]ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. N,N′-dimethyl-N-pyridin-2-ylethane-1,2-diamine

A mixture of 2-fluoropyridine (0.485 g, 5 mmol),N,N′-dimethyl-1,2-ethanediamine (1.32 g, 15 mmol) and sodium carbonate(1.59 g, 15 mmol) in 1,4-dioxane (5 mL) was heated under refluxovernight. The mixture was filtered and the filtrate was concentrated.The residue was co-evaporated with 1,4-dioxane (×2), and then dried togive the desired product (810 mg, 98%).

Step 2.2-Fluoro-N-methyl-N-2-[methyl(pyridin-2-yl)amino]ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=472.3.

Example 174:2-Chloro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. methyl 4-(2-aminopyrimidin-5-yl)-2-chlorobenzoate

A solution of potassium carbonate (0.39 g, 2.8 mmol) in water (3 mL) wasadded to a mixture of methyl 4-bromo-2-chlorobenzoate (0.49 g, 2.0mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(0.31 g, 1.4 mmol), and tetrakis(triphenylphosphine)palladium (0.08 g,0.07 mmol) in toluene (5.3 mL) and ethanol (3 mL). The resulting mixturewas heated at 120° C. for 15 min. The reaction mixture was extractedwith EtOAc (3×20 mL). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was recrystallized from methanol and ether. The precipitate wascollected by filtration, and washed with ether to afford the desiredproduct (0.22 g, 59%). LCMS: (M+H)=264.0/266.0.

Step 2. methyl2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate

A mixture of methyl 4-(2-aminopyrimidin-5-yl)-2-chlorobenzoate (0.22 g,0.83 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.20 g,0.83 mmol) in ethanol (6 mL) was stirred at 100° C. overnight. Thereaction mixture was concentrated to afford the crude product which wasdirectly used for next step. LCMS: (M+H)=455.1/457.1.

Step 3.2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid

A mixture of methyl2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate(180.4 mg, 0.41 mmol) and lithium hydroxide monohydrate (34 mg, 0.82mol) in methanol (0.99 mL) and water (0.33 mL) was stirred at 40° C. forabout 3 h. The mixture was adjusted to pH 5 by adding 4N HCl in1,4-dioxane. The volatiles were removed under reduced pressure. Theresidue was dried to give a crude product which was contaminated withLiCl and was directly used for next step without further purification.LCMS: (M+H)=441.0/443.0.

Step 4.2-chloro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (14 μL, 0.081 mmol) was added to a mixture of2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid (0.027 mmol), methylamine (2M in THF, 0.2 mL, 0.4 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(14 mg, 0.032 mmol) in N,N-dimethylformamide (0.5 mL). The mixture wasstirred at RT for 2 h, and then purified by RP-HPLC (pH 10) to affordthe desired product. LCMS: (M+H)=454.1/456.0.

Example 175:2-Chloro-N-cyclopropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=480.1/482.0.

Example 176:2-Chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-(tetrahydrofuran-3-yl)benzamide

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=510.0/512.1.

Example 177:2-Chloro-N-(1-pyridin-2-ylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=545.1/547.1.

Example 178:6-(1-{6-[4-(Azetidin-1-ylcarbonyl)-3-chlorophenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=480.1/482.0.

Example 179:2-Chloro-N-(1-pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=586.0/588.1.

Example 180:2-Chloro-N-[1-methyl-2-(pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=575.1/577.1.

Example 181:2-Chloro-N-(1S)-1-[(dimethylamino)carbonyl]-2-methylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 174. LCMS:(M+H)=567.1/569.1.

Example 182:2-Cyclopropyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one

Step 1. methyl 4-bromo-2-(bromomethyl)benzoate

A mixture of methyl 4-bromo-2-methylbenzoate (0.7 g, 0.003 mol),N-bromosuccinimide (0.65 g, 0.0037 mol) and benzoyl peroxide (0.038 g,0.00016 mol) in carbon tetrachloride (30 mL) was refluxed under anatmosphere of nitrogen for 2 h. The mixture was cooled to RT, andfiltered through silica gel eluting with dichloromethane followed bydiethyl ether. The mixture was concentrated and the residue was purifiedby chromatography on silica gel with 30% EtOAc in hexanes to afford thedesired product (0.86 g, 90%).

Step 2. 5-bromo-2-cyclopropylisoindolin-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.13 g, 0.42 mmol),cyclopropylamine (0.034 mL, 0.49 mmol) and potassium carbonate (0.090 g,0.65 mmol) in ethanol (0.9 mL) was stirred at 40° C. for 3 h. Thereaction mixture was quenched with saturated sodium bicarbonate andextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by chromatography on silica gel with 30% EtOAc inhexanes to afford the desired product (0.10 g, 94%). LCMS:(M+H)=252.0/254.0.

Step 3. 5-(2-aminopyrimidin-5-yl)-2-cyclopropylisoindolin-1-one

A solution of potassium carbonate (0.10 g, 0.75 mmol) in water (0.7 mL)was added to a mixture of 5-bromo-2-cyclopropylisoindolin-1-one (0.095g, 0.38 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.12g, 0.56 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02mmol) in toluene (1.4 mL) and ethanol (0.7 mL). The resulting mixturewas heated at 120° C. for 15 min. The reaction mixture was then quenchedwith saturated sodium bicarbonate (5 mL) and extracted with EtOAc. Theorganic layers were washed with brine, dried with anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by chromatographyon silica gel with 10% methanol in dichloromethane to afford the desiredproduct (0.046 g, 46%). LCMS: (M+H)=267.1.

Step 4. 2-cyclopropyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one

A mixture of 5-(2-aminopyrimidin-5-yl)-2-cyclopropylisoindolin-1-one (20mg, 0.075 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (18mg, 0.075 mmol) in isopropyl alcohol (0.5 mL) was stirred at 90° C.overnight. The reaction mixture was purified by RP-HPLC (pH 10) toafford the desired product. LCMS: (M+H)=458.1.

Example 183:2-Ethyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one

This compound was prepared from methyl 4-bromo-2-(bromomethyl)benzoateusing procedures analogous to those for Example 182. LCMS: (M+H)=446.1.

Example 184:2-(2-Methoxy-1-methylethyl)-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one

This compound was prepared from methyl 4-bromo-2-(bromomethyl)benzoateusing procedures analogous to those for Example 182. LCMS: (M+H)=490.2.

Example 185:2-(Pyridin-2-ylmethyl)-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one

This compound was prepared from methyl 4-bromo-2-(bromomethyl)benzoateusing procedures analogous to those for Example 182. LCMS: (M+H)=509.1.

Example 186:2-Methyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one

This compound was prepared from methyl 4-bromo-2-(bromomethyl)benzoateusing procedures analogous to those for Example 182. LCMS: (M+H)=432.1.

Example 187:N-Ethyl-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide

Step 1. tert-butyl1-[4-(2-aminopyrimidin-5-yl)phenyl]cyclopropanecarboxylate

A solution of sodium carbonate (0.56 g, 0.0052 mol) in water (5.0 mL)was added to a mixture of tert-butyl1-(4-bromophenyl)cyclopropanecarboxylate (0.78 g, 0.0026 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.87g, 0.0039 mol), and tetrakis(triphenylphosphine)palladium (0.2 g, 0.0001mol) in toluene (10 mL) and ethanol (5 mL). The resulting mixture washeated at 120° C. for 15 min, quenched with water (5 mL), and washedwith ether (3×10 mL). The precipitate in the aqueous layer was filtered,washed with water, and dried to afford the desired product (0.40 g,60%). LCMS: (M+H)=256.1.

Step 2.1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylicacid

A mixture of 1-[4-(2-aminopyrimidin-5-yl)phenyl]cyclopropanecarboxylicacid (0.22 g, 0.86 mmol) andchloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.21 g, 0.86 mmol) inethanol (8 mL) was stirred at 100° C. overnight. The reaction mixturewas purified by RP-HPLC (pH 10) to afford the desired product (0.12 g,31%). LCMS: (M+H)=447.1.

Step 3.N-ethyl-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide

A mixture of1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylicacid (20 mg, 0.045 mmol), ethylamine (2.4 mg, 0.054 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(24 mg, 0.054 mmol), and N,N-diisopropylethylamine (23 μL, 0.13 mmol) inN,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reactionmixture was purified by RP-HPLC (pH 10) to afford the desired product.LCMS: (M+H)=474.1.

Example 188:N-(1-Pyridin-2-ylethyl)-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide

This compound was prepared from1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylicacid using procedures analogous to those for Example 187. LCMS:(M+H)=551.2.

Example 189:N-[1-Methyl-2-(pyridin-2-yloxy)ethyl]-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide

This compound was prepared from1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylicacid using procedures analogous to those for Example 187. LCMS:(M+H)=581.2.

Example 190:2-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-2-hydroxy-N-methylacetamide

Step 1. 2-(4-bromo-2-fluorophenyl)-2-hydroxy-N-methylacetamide

N,N-Diisopropylethylamine (0.2 mL, 0.001 mol) was added to a mixture of(4-bromo-2-fluorophenyl)(hydroxy)acetic acid (0.1 g, 0.4 mmol),methylamine (2M in THF, 0.24 mL, 0.48 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.21 g, 0.00048 mol) in methylene chloride (2 mL). The mixture wasstirred at RT for 2 h. The reaction mixture was concentrated. Theresidue was purified by chromatography on silica gel with 10% methanolin dichloromethane to afford the desired product. LCMS:(M+H)=261.9/263.9.

Step 2.2-[4-(2-aminopyrimidin-5-yl)-2-fluorophenyl]-2-hydroxy-N-methylacetamide

A mixture of 2-(4-bromo-2-fluorophenyl)-2-hydroxy-N-methylacetamide (0.4mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(0.11 μg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (0.01 g,0.01 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in toluene (0.6mL) and 1,4-dioxane (0.6 mL) was heated at 100° C. for 1.5 h. Aftercooling to RT, the mixture was filtered through a pad of silica gel,washed with 10% methanol in dichloromethane. The filtrate wasconcentrated under reduced pressure and the residue purified bychromatography on silica gel with 10% methanol in dichloromethane toafford the desired product. LCMS: (M+H)=277.0.

Step 3. 2-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl-2-hydroxy-N-methylacetamide

A mixture of2-[4-(2-aminopyrimidin-5-yl)-2-fluorophenyl]-2-hydroxy-N-methylacetamide(18 mg, 0.066 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde(19 mg, 0.079 mmol) in ethanol (0.4 mL) was stirred at 90° C. overnight.The reaction mixture was purified by RP-HPLC (pH 10) to afford thedesired product. LCMS: (M+H)=468.1.

Example 191:2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-2-hydroxy-N,N-dimethylacetamide

This compound was prepared from (4-bromo-2-fluorophenyl)(hydroxy)aceticacid using procedures analogous to those for Example 190. LCMS:(M+H)=482.1.

Example 192:N-(3-[2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)-N′-ethylurea

Step 1. tert-butyl [3-(3-oxopropyl)phenyl]carbamate

Tris(dibenzylideneacetone)dipalladium (0.10 g, 0.00011 mol) andtri-tert-butylphosphonium tetrafluoroborate (0.064 g, 0.00022 mol) in aflask was evacuated and refilled with N₂ (3 times). Then 1,4-dioxane(7.0 mL) was added followed by consecutive addition of tert-butyl(3-bromophenyl)carbamate (2.00 g, 0.00735 mol), 2-propen-1-ol (0.854 g,0.0147 mol), N-cyclohexyl-N-methyl-cyclohexanamine (1.7 g, 0.0088 mol).The reaction mixture was stirred at 40° C. overnight, filtered, andwashed with dichloromethane. The filtrate was concentrated and purifiedby chromatography on silica gel with 40% EtOAc in hexanes to afford thedesired product (0.5 g, 30%).

Step 2. tert-butyl [3-(2-chloro-3-oxopropyl)phenyl]carbamate

N-Chlorosuccinimide (0.27 g, 0.0020 mol) was added to a mixture oftert-butyl [3-(3-oxopropyl)phenyl]carbamate (0.50 g, 0.0020 mol) andD-proline (0.05 g, 0.0004 mol) in methylene chloride (5 mL) at 0° C. Thereaction mixture was stirred at RT for 2 h and concentrated. The residuewas purified by chromatography on silica gel with 30% EtOAc in hexanesto afford the desired product (0.50 g, 88%). LCMS: (M+H)=209.9/211.9.

Step 3. tert-butyl(3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)carbamate

A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (19 mg,0.070 mmol) and tert-butyl [3-(2-chloro-3-oxopropyl)phenyl]carbamate (20mg, 0.070 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C. Thereaction mixture was purified by RP-HPLC (pH 10) to afford the desiredproduct. LCMS: (M+H)=498.0/500.0.

Step 4.3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylaniline

A mixture of tert-butyl(3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)carbamate(10 mg, 0.02 mmol) in trifluoroacetic acid (0.5 mL) and methylenechloride (0.5 mL) was stirred overnight at RT. The mixture wasconcentrated to afford the desired product as a TFA salt which wasdirectly used for next step. LCMS: (M+H)=397.9/399.9.

Step 5.N-(3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)-N′-ethylurea

Isocyanatoethane (1.3 μL, 0.019 mmol) were added to a mixture of3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylaniline(5 mg, 0.01 mmol) and triethylamine (7.0 μL, 0.050 mmol) in acetonitrile(0.5 mL). After the reaction mixture was stirred at RT for 30 min, itwas purified by RP-HPLC (pH 10) to afford the desired product (2 mg,30%). LCMS: (M+H)=469.0/470.8.

Example 193:2-(2,3-Dichlorophenyl)-7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-][1,2,4]triazin-3-amine

A mixture of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (19 mg,0.076 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (22 mg,0.091 mmol) in ethanol (0.50 mL) was stirred at 105° C. overnight. Thereaction mixture was purified by RP-HPLC (pH 10) to afford the desiredproduct (12 mg, 35%). LCMS: (M+H)=447.3/449.2/451.2.

Example 194:2,3-Difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1.1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione

To a cooled (0° C.) mixture of (1-quinolin-6-ylcyclopropyl)acetaldehyde(9.9 g, 47 mmol), D-proline (1.1 g, 9.4 mmol) in chloroform (200 mL) wasadded N-chlorosuccinimide (6.26 g, 46.9 mmol). The mixture was stirredat 0° C. for 30 min and then gradually warmed to RT for 2 h. Thereaction mixture was quenched with saturated sodium bicarbonate (25 mL)and extracted with EtOAc (3×100 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Theprecipitate formed was filtered to give the desired product. Thefiltrate was chromatographed on silica gel with EtOAc in methylenechloride (10%) to afford chloro(1-quinolin-6-ylcyclopropyl)acetaldehydewhich was contaminated with pyrrolidine-2,5-dione (13.0 g), andautomatically converted to the desired product after a few days. Thetotal desired product obtained is 16 g. LCMS: (M+H)=345.0/347.0.

Step 2. 4-(2-aminopyrimidin-5-yl)-2,3-difluorobenzoic acid

A mixture of 4-(dihydroxyboryl)-2,3-difluorobenzoic acid (0.47 g, 2.3mmol), 5-bromopyrimidin-2-amine (0.44 g, 2.6 mmol),tetrakis(triphenylphosphine)palladium (0.1 g, 0.1 mmol), and potassiumcarbonate (0.96 g, 7.0 mmol) in toluene (4.0 mL), ethanol (2.0 mL) andwater (2.0 mL) was heated at 110° C. for 3 h. After cooling to RT, themixture was washed with ether to remove impurity. The aqueous layer wasadjusted to pH 6 with 1N HCl. The solid was filtered, washed with waterand ether to give the desired product. LCMS: (M+H)=252.9.

Step 3.2,3-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid

A mixture of 4-(2-aminopyrimidin-5-yl)-2,3-difluorobenzoic acid (15 mg,0.060 mmol) and1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione(20 mg, 0.058 mmol) in ethanol (1.0 mL) was stirred at 100° C.overnight. The reaction mixture was purified by RP-HPLC (pH 10) toafford the desired product (9 mg, 40%). LCMS: (M+H)=443.0.

Step 4. 2,3-difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[,2-a]pyrimidin-6-yl]benzamide

A mixture of2,3-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid (9.0 mg, 0.020 mmol), methylamine (2M in THF, 0.02 mL, 0.041 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(11 mg, 0.024 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol) inN,N-dimethylformamide (0.5 mL) was stirred at RT for 4 h. The reactionmixture was purified by RP-HPLC (pH 10) to afford the desired product.LCMS: (M+H)=456.0.

Example 195:6-Difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from 4-(dihydroxyboryl)-2,6-difluorobenzoicacid using procedures analogous to those for Example 194. LCMS:(M+H)=456.0.

Example 196:2-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzenesulfonamide

Step 1. 4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzenesulfonamide

4-Bromo-2-fluorobenzenesulfonyl chloride (100 mg, 0.36 mmol) was addedto a mixture of methylamine (2M in THF, 0.275 mL, 0.55 mmol) andtriethylamine (0.10 mL, 0.73 mmol) in methylene chloride (2.0 mL). Thereaction mixture was quenched with saturated NaHCO₃ (1.0 mL) andconcentrated to afford the crude intermediate in water. A mixture of theintermediate in water,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (81 mg,0.36 mmol), tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol),potassium carbonate (150 mg, 1.1 mmol) in toluene (2.0 mL) and ethanol(1.0 mL) was heated at 110° C. for 2 h. After cooling to RT, ether wasadded to the mixture and the solid was filtered, washed with water andether to afford the desired product (0.086 g, 83%). LCMS: (M+H)=282.9.

Step 2.2-fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzenesulfonamide

A mixture of4-(2-aminopyrimidin-5-yl)-2-fluoro-N-methylbenzenesulfonamide (20 mg,0.07 mmol) and1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione(24 mg, 0.07 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C.The reaction mixture was purified by RP-HPLC (pH 10) to afford thedesired product. LCMS: (M+H)=474.0.

Example 197:N,N-Dimethyl-2-{3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}acetamide

Step 1. tert-butyl [3-(2-aminopyrimidin-5-yl)-1H-pyrazol-1-yl]acetate

To a solution of 1H-pyrazol-5-ylboronic acid (0.2 g, 2 mmol) inN,N-dimethylformamide (1.0 mL) were added 1,1-dimethylethyl bromoacetate(0.38 g, 2 mmol) and potassium carbonate (0.74 g, 0.0054 mol). Thereaction mixture was stirred overnight at RT. To the reaction mixturewas added 5-bromopyrimidin-2-amine (0.40 g, 2.3 mmol) andtetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol). The resultingmixture was stirred at 100° C. for 2 h. After cooling to RT, thereaction mixture was extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by RP-HPLC toafford the desired product. LCMS: (M+H)=276.0.

Step 2. tert-butyl 3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[,2-a]pyrimidin-6-yl]-1H-pyrazol-1-ylacetate

A mixture of tert-butyl[3-(2-aminopyrimidin-5-yl)-1H-pyrazol-1l-yl]acetate (16 mg, 0.058 mmol)and1-[2-chloro-1-hydroxy-2-(1-quinolin-6-ylcyclopropyl)ethyl]pyrrolidine-2,5-dione(20 mg, 0.058 mmol) in ethanol (0.3 mL) was stirred overnight at 105° C.The reaction mixture was purified by RP-HPLC (pH 10) to afford thedesired product (10 mg, 37%). LCMS: (M+H)=467.0.

Step 3. N,N-dimethyl-2-{3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}acetamide

A mixture of tert-butyl3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-ylacetate(10 mg, 0.02 mmol) in trifluoroacetic acid (0.5 mL) and methylenechloride (0.5 mL) was stirred overnight at RT. The volatiles wereremoved under reduced pressure. The residue [LCMS: (M+H)=411.0] wasdissolved in N,N-dimethylformamide (0.5 mL) and treated withdimethylamine (2M in THF, 0.016 mL, 0.032 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(11 mg, 0.026 mmol), and N,N-diisopropylethylamine (11 μL, 0.064 mmol).The reaction mixture was stirred overnight at RT, and then purified byRP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=438.1.

Example 198:N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. tert-butyl(2S)-2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)-3,3-dimethylbutanoate

This compound was prepared from2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoicacid using procedures analogous to those for Example 163. LCMS:(M+H)=594.2.

Step 2.(2S)-2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)-3,3-dimethylbutanoicacid

A mixture of tert-butyl(2S)-2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)-3,3-dimethylbutanoate(60 mg, 0.1 mmol) in 2.0 ml of 4N HCl in 1,4-dioxane was stirred for 1h. The mixture was concentrated to give the desired product as an HClsalt. LCMS: (M+H)=538.1.

Step 3.N-[(1S)-1-(azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (14 μL, 0.084 mmol) was added to a mixture of(2S)-2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)-3,3-dimethylbutanoicacid (15 mg, 0.028 mmol), azetidine hydrochloride (3.9 mg 0.042 mmol),and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (18 mg, 0.042 mmol) in N,N-dimethylformamide (0.5mL). After stirring at RT overnight, the reaction mixture was purifiedby RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=577.2.

Example 199:N-[2-(Dimethylamino)-1-methyl-2-oxoethyl]-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

Step 1. methyl 2-[(4-bromo-2-fluorobenzoyl)amino]propanoate

N,N-Diisopropylethylamine (2.0 mL, 0.011 mol) was added to a mixture ofmethyl 2-aminopropanoate hydrochloride (0.64 g, 0.0046 mol),4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(2.12 g, 0.00479 mol) in N,N-dimethylformamide (10.0 mL, 0.129 mol). Thereaction mixture was stirred overnight at RT, quenched with saturatedsodium bicarbonate (25 mL) and extracted with EtOAc (3×40 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified bychromatography on silica gel with 60% EtOAc in hexanes to afford thedesired product (1.33 g, 96%). LCMS: (M+H)=303.9/305.9.

Step 2. 2-{[4-(2-aminopyrimidin-5-yl)-2-fluorobenzoyl]amino}propanoicacid

A solution of potassium carbonate (0.35 g, 2.5 mmol) in water (2 mL) wasadded to a mixture of methyl2-[(4-bromo-2-fluorobenzoyl)amino]propanoate (0.5 g, 1.6 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.28g, 1.3 mmol), and tetrakis(triphenylphosphine)palladium (0.07 g, 0.06mmol) in toluene (4 mL) and ethanol (2 mL). The resulting mixture washeated at 120° C. for 15 min. The reaction mixture was extracted withether (3×10 mL) to remove impurity. The aqueous layer was adjusted to pH7 with aqueous HCl and purified by RP-HPLC (pH 10) to afford the desiredproduct (0.40 g, 100%). LCMS: (M+H)=305.0.

Step 3.2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoicacid

A mixture of 2-[4-(2-aminopyrimidin-5-yl)-2-fluorobenzoyl]aminopropanoicacid (0.20 g, 0.66 mmol) andchloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.19 g, 0.79 mmol) inethanol (4.0 mL) was stirred overnight at 90° C. The mixture wasconcentrated to afford the crude product. LCMS: (M+H)=496.1.

Step 4.N-[2-(dimethylamino)-1-methyl-2-oxoethyl]-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

N,N-Diisopropylethylamine (31 μL, 0.18 mmol) was added to a mixture of2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoicacid (29.7 mg, 0.06 mmol), dimethylamine (4.0 mg, 0.09 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(40 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL). The reactionmixture was stirred overnight at RT and purified by RP-HPLC (pH 10) toafford the desired product. LCMS: (M+H)=523.1.

Example 200:N-(2-Azetidin-1-yl-1-methyl-2-oxoethyl)-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoicacid using procedures analogous to those for Example 199. LCMS:(M+H)=535.1.

Example 201:2-Fluoro-N-2-[(3R)-3-methoxypyrrolidin-1-yl]-1-methyl-2-oxoethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide

This compound was prepared from2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoicacid using procedures analogous to those for Example 199. LCMS:(M+H)=579.2.

Example 202:2-Fluoro-N-[(1-hydroxycyclopropyl)methyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

This compound was prepared as a TFA salt starting from4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoicacid using procedures analogous to those for Example 123. LCMS:(M+H)=469.1.

Example 203: Methyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Step 1. tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate

To a solution of 1.0 M of potassium tert-butoxide in THF (26.3 mL) at 0°C. was added drop wise a solution of diethyl cyanomethylphosphonate(4.47 mL, 0.0276 mol) in THF (33.6 mL). The reaction was warmed to RTand then cooled at 0° C. again. To the reaction mixture was then added asolution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.0 g, 0.025 mol)in THF (6.72 mL). The reaction was allowed to warm up to RT and stirredovernight. After being quenched with water, the mixture was extractedwith EtOAc. The combined organic layers were washed with brine, dried,and concentrated. The crude mixture was purified on silica gel elutingwith EtOAc in hexanes (0-60%) to give the desired product (5.4 g,96.81%). LCMS: (M+Na)=244.9, (M−56+H)=167.0.

Step 2. tert-butyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

1,8-Diazabicyclo[5.4.0]undec-7-ene (68 μL, 0.46 mmol) was added to amixture of6-[2-(1H-pyrazol-4-yl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoline(50.0 mg, 0.153 mmol) and tert-butyl4-(cyanomethylene)piperidine-1-carboxylate (0.068 g, 0.30 mmol) inacetonitrile (1 mL). The reaction was stirred at 60° C. overnight. Aftercooling to RT, the mixture was purified by chromatography on silica gelwith EtOAc in CH₂Cl₂ (0-70%) to give the desired product (30 mg, 35.7%).LCMS: (M+H)=550.5.

Step 3.(4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrile

Trifluoroacetic Acid (0.5 mL) was added to a solution of tert-butyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate(0.015 g, 0.000027 mol) in methylene chloride (0.5 mL). The mixture wasstirred at RT for 0.5 h. The volatiles were removed under reducedpressure to give the desired product as a TFA salt which was directlyused in the next step without further purification. LCMS: (M+H)=450.5.

Step 4. Methyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Methyl chloroformate (2.6 μL, 0.033 mmol) was added to a solution of(4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrile(5.0 mg, 0.011 mmol) and triethylamine (6.2 μL, 0.044 mmol) in methylenechloride (0.5 mL). The mixture was stirred at RT for 1 h, and thenpurified by RP-HPLC (pH=2) to give the desired product as a TFA salt.LCMS: (M+H)=508.5.

Example 204: Ethyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

This compound was prepared as a TFA salt starting from(4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrileusing procedures analogous to those for Example 203, Step 4. LCMS:(M+H)=522.4.

Example 205:(1-Acetyl-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrile

This compound was prepared as a TFA salt starting from(4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrileusing procedures analogous to those for Example 203, Step 4. LCMS:(M+H)=492.4.

Example A

In Vitro c-Met Kinase Enzyme Assays

Compounds were screened in vitro for their ability to inhibit c-Metkinase activity. The IC₅₀ values of compounds for the inhibition ofc-Met kinase were determined as described in the literature with somemodifications (Wang, X. et al, Mol. Cancer Ther. 2003, 2(11):1085-1092;Calic, M. et al., Croatica Chemical ACTA. 2005, 78(3):367-374). Briefly,histidine-tagged c-Met catalytic domain fusion protein (Invitrogen, #PV3143) was used for the assay. IC₅₀ measurements were based on thedegree of phosphorylation of poly Glu-Tyr (Sigma-Aldrich, # P0275) thatwas coated (0.01 mg/per well) on 96-well microplates (R&D systems, #DY990). The reaction was carried out in a 50 μL solution containing 50mM HEPES (pH 7.5), 10 mM MnCl₂, 10 mM MgCl₂, 0.5 mM DTT, 100 μM Na₃VO₄,5 μM ATP (Cell Signaling Technology, #9804) and serial dilutions ofindividual compounds. The reaction lasted for 25 minutes at 30° C. Afterthe reaction was completed, the contents of the plates was discarded.Plates were then washed with TBS-T (250 μL/well, 5×) and then blockedwith TBS-T containing 1% BSA for 2 hours. The contents of the plates wasdiscarded, and 100 μL (per well) of peroxidase-labeledanti-phospho-tyrosine antibody (Sigma, # A5964) diluted (1:60,000) in 1%BSA containing TBS-T were then added and incubated for 1 hour. Plateswere washed with TBS-T (250 μL/well, 5×) and followed by the colorreaction using 100 μL (1:1 mixture) of H₂O₂ and tetramethylbenzidine(R&D Systems, # DY999). The reaction was stopped in minutes with 100 μLof 2 N H₂SO₄. The optical density was measured immediately using amicroplate reader at 450 nm with wavelength correction at 540 nm. IC₅₀values were calculated with the GraphPad Prism software. The linearrange (i.e., the time period over which the rate remained equivalent tothe initial rate) was determined for the kinase and IC₅₀ determinationswere performed within this range.

-   Wang, X., et al. Potent and selective inhibitors of the Met    [hepatocyte growth factor/scatter factor (HGF/SF) receptor]tyrosine    kinase block HGF/SF-induced tumor cell growth and invasion. Mol.    Cancer Ther. 2003, 2(11):1085-1092.-   Calic, M., et al. Flavonoids as inhibitors of Lck and Fyn kinases.    Croatica Chemica ACTA. 2005, 78(3):367-374.

IC₅₀ data for certain compounds of the invention is provided below.

h-Met IC₅₀ Example (nM) 1 <500 2 <500 3 <500 4 <500 5 <500 6 <500 7 <5008 <500 9 <500 10 <500 11 <500 12 <500 13 <500 14 <500 15 <500 16 <300017 <500 18 <500 19 <500 20 <500 21 <500 22 <500 23 <500 24 <500 25 <50026 <500 27 <500 28 <500 29 <500 30 <500 31 <500 32 <500 33 <500 34 <50035 <500 36 <500 37 <500 38 <500 39 <500 40 <500 41 <500 42 <500 43 <50044 <500 45 <500 46 <500 47 <500 48 <500 49 <500 50 <500 51 <500 52 <50053 <500 54 <500 55 <500 56 <500 57 <500 58 <500 59 <500 60 <500 61 <50062 <500 63 <500 64 <500 65 <500 66 <500 67 <500 68 <500 69 <500 70 <50071 <500 72 <500 73 <500 74 <500 75 <500 76 <500 77 <500 78 <500 79 <50080 <500 81 <2000 82 <500 83 <500 84 <500 85 <500 86 <500 87 <500 88 <50089 <3000 90 <500 91 <500 92 <500 93 <500 94 <500 95 <500 96 <500 97 <50098 <500 99 <500 100 <500 101 <500 102 <500 103 <500 104 <500 105 <500106 <500 107 <500 108 <500 109 <500 110 <500 111 <500 112 <500 113 <500114 <500 115 <500 116 <500 117 <500 118 <500 119 <500 120 <500 121 <500122 <500 123 <500 124 <500 125 <500 126 <500 127 <500 128 <500 129 <500130 <500 131 <500 132 <500 133 <500 134 <500 135 <500 136 <500 137 <500138 <500 139 <500 140 <500 141 <500 142 <500 143 <500 144 <500 145 <500146 <500 147 <500 148 <500 149 <500 150 <500 151 <500 152 <500 153 <500154 <500 155 <500 156 <500 157 <500 158 <500 159 <500 160 <500 161 <500162 <500 163 <500 164 <500 165 <500 166 <500 167 <500 168 <500 169 <500170 <500 171 <500 172 <500 173 <500 174 <500 175 <500 176 <500 177 <500178 <500 179 <500 180 <500 181 <500 182 <500 183 <500 184 <500 185 <500186 <500 187 <500 188 <500 189 <500 190 <500 191 <500 192 <500 193 <500194 <500 195 <500 196 <500 197 <500 198 <500 199 <500 200 <500 201 <500202 <500 203 <500 204 <500 205 <500

Example B Cell Proliferation/Survival Assays

Cell lines representing various human cancers (SNU-1 and SUN-5 gastric,A549 and NCI-H441 lung, U-87 glioblastoma, HT-29 colon, 786-0 kidney,PC-3 pancreatic) can be obtained from American Type Culture Collectionand routinely maintained in culture media and conditions recommended byATCC. Optimal cell density used in proliferation/survival assay can bepredetermined for individual cell lines. Compounds are screened fortheir ability to inhibit cell proliferation/survival, and IC₅₀ valuesare determined. Below are the sample protocols for SNU-5 and SNU-1 cellproliferation/survival assays. SNU-5 and SNU-1 cells are seeded into 96well cell culture plates at 4000 cells/well and 2000 cells/wellrespectively in appropriate media containing 2% FBS and supplementedwith serial dilutions of individual compounds in a final volume of 100μL/well. After 72 hour incubation, 24 μL of CellTiter 96® AQueous OneSolution reagent (Promega, # G3581) are added to each well (finalconcentration=333 g/mL), and the plates are incubated for 2 more hoursin a 37° C. incubator. The optical density is measured in the linearrange using a microplate reader at 490 nm with wavelength correction at650 nm. IC₅₀ values are calculated with the GraphPad Prism software. Forproliferation assays using A549, NCI-H441, U-87, HT-29, 786-0 and PC-3cells, the cells are first starved for 48 hours in low serum condition(0.1-0.5% FBS in appropriate culture media), then treated with differentconcentrations of compounds for 2 hours. After the cells are treatedwith HGF (50 ng/mL) (R&D, #294-HGN) for 24 hours, CellTiter 96® AQueousOne Solution reagent is added and plates are incubated for 2 hours. Theresults are recorded with a plate reader. Compounds having an IC₅₀ of 10μM or less are considered active.

Example C

Cell-Based c-Met Phosphorylation Assays

The inhibitory effect of compounds on c-Met phosphorylation in relevantcell lines (SNU-5 gastric, A549 and NCI-H441 lung, U-87 glioblastoma,HT-29 colon, 786-0 kidney and PC-3 pancreatic cancer cell lines andHUVEC cell line) can be assessed using immunoblotting analysis andELISA-based c-Met phosphorylation assays. Cells are grown in appropriateculture media and treated with various concentrations of individualcompounds. For SNU-5, HT-29, 786-0 cells, cells are grown inappropriated media supplemented with 0.2% or 2% FBS and treated withcompounds for 3-4 hours. Whole cell protein extracts are prepared usingreagents and a protocol (# FNN0011) obtained from BiosourceInternational with slight modifications. Briefly, protein extracts aremade by incubation in lysis buffer with protease and phosphataseinhibitors [50 mM HEPES (pH 7.5), 100 mM NaCl, 1.5 mM MgCl₂, 10%Glycerol, 1% Triton X-100, 1 mM sodium orthovanadate, 1 mM sodiumfluoride, aprotinin (2 μg/mL), leupeptin (2 μg/mL), pepstatin A (2μg/mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4° C. Proteinextracts are cleared of cellular debris by centrifugation at 14,000×gfor 20 minutes. For A549, H441, U-87 and PC-3 cells, cells are serum(0.2% FBS) starved for at least 24 hours, then pretreated with variousconcentrations of compounds for 1 hour. Whole cell extracts are preparedafter the cells were treated with HGF (50 ng/mL) for 10 minutes.

Immunoblotting Analysis

Relevant antibodies are obtained from commercial sources: rabbitpolyclonal antibodies included anti-human c-Met (Santa CruzBiotechnology, # sc-161) and anti-phosphorylated-c-Met (BiosourceInternational, pY1230/4/5 and pY1003). For immunoblotting, 10-20 μg ofprotein extracts from individual treatment conditions are resolved byelectrophoresis on 10% SDS-PAGE gel, and electrotransferred to anitrocellulose (or PVDF) membrane. The membrane is blocked in PBScontaining 3% milk and 0.1% Tween-20 for 1 hour, and then incubated withprimary anti-c-Met antibodies in blocking solution for 1 hour. After 3washes, the membrane is incubated with appropriatehorseradish-conjugated secondary antibodies for 1 hour. After finalwash, the blot is incubated with chemiluminescence detection reagent for5 minutes and exposed to X-ray film. The images are scanned, quantifiedand corrected with total c-Met, and IC₅₀ values are calculated.Compounds having an IC₅₀ of 10 M or less are considered active.

ELISA

Cell protein extracts are analyzed using a human phospho-c-Met ELISA kitaccording to the manufacturer's instructions (R&D Systems, #DYC2480).Optimal amounts of protein extracts are predetermined for individualcell lines. Briefly, for the assay, appropriate amounts of proteinextracts are captured with a capture anti-human c-Met antibody for 2hours in a 96 well microplate. After washes, a detection antibody(HRP-conjugated anti-phospho-tyrosine antibody) is added and incubatedfor 2 hours. After additional washes, 100 μL of substrate solution (1:1mixture of H₂O₂ and tetramethylbenzidine) are added into each well andthe reaction is stopped with 2 N H₂SO₄ within an appropriate amount oftime during color development. The optical density is measured in thelinear range using a microplate reader at 450 nm with wavelengthcorrection at 540 nm. IC₅₀ values are calculated with the GraphPad Prismsoftware. Compounds having an IC₅₀ of 10 μM or less are consideredactive.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is: 1-72. (canceled)
 73. A method of treating gastriccancer, cancer of the kidney, liver cancer, lung cancer, or glioblastomain a patient comprising administering to said patient a therapeuticallyeffective amount of a compound of Formula I:

or pharmaceutically acceptable salt thereof or prodrug thereof, wherein:A is N or CR³; Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl,each optionally substituted by 1, 2, 3, 4, or 5 —W—X—Y—Z; Cy² is aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substitutedby 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′; L¹ is (CR⁴R⁵)_(m),(CR⁴R⁵)_(p)-(cycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(arylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heterocycloalkylene)-(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)-(heteroarylene)-(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)O(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)C(O)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)C(O)O(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)OC(O)(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)OC(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)NR⁶(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)NR⁶C(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(O)(CR⁴R⁵)_(q), (CR⁴R⁵)_(p)S(O)NR⁶(CR⁴R⁵)_(q),(CR⁴R⁵)_(p)S(O)₂(CR⁴R⁵)_(q), or (CR⁴R⁵)_(p)S(O)₂NR⁶(CR⁴R⁵)_(q), whereinsaid cycloalkylene, arylene, heterocycloalkylene, or heteroarylene isoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d), P(R^(f))₂,P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); L²is (CR⁷R⁸)_(r), (CR⁷R⁸)_(s)-(cycloalkylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(arylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(heterocycloalkylene)-(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)-(heteroarylene)-(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)O(CR⁷R⁸)_(t),(CR⁷R⁸),S(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)C(O)(CR⁷R⁸)_(t),(CR⁷R⁸)SC(O)NR⁹(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)C(O)O(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)OC(O)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)OC(O)NR⁹(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)NR⁹(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)NR⁹C(O)NR⁹(CR⁷R⁸)_(t),(CR⁷R⁸)_(s)S(O)(CR⁷R⁸)_(t), (CR⁷R⁸)_(s)S(O)NR⁷(CR⁸R⁹)_(t),(CR⁷R⁸)_(s)S(O)₂(CR⁷R⁸)_(t), or (CR⁷R⁸)_(s)S(O)₂NR⁹(CR⁷R⁸)_(t), whereinsaid cycloalkylene, arylene, heterocycloalkylene, or heteroarylene isoptionally substituted with 1, 2, or 3 substituents independentlyselected from Cy⁴, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)C(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); R¹ is H or—W″—X″—Y″—Z″; R² is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, CN, NO₂, OR^(A), SR^(A), C(O)R^(B), C(O)NR^(C)R^(D),C(O)OR^(A), OC(O)R^(B), OC(O)NR^(C)R^(D), NR^(C)R^(D), NR^(C)C(O)R^(B),NR^(C)C(O)NR^(C)R^(D), NR^(C)C(O)OR^(A), S(O)R^(B), S(O)NR^(C)R^(D),S(O)₂R^(B), NR^(C)S(O)₂R^(B), or S(O)₂NR^(C)R^(D); R³ is H, cycloalkyl,aryl, heterocycloalkyl, heteroaryl, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(A), SR^(A), C(O)R^(B),C(O)NR^(C)R^(D), C(O)OR^(A), OC(O)R^(B), OC(O)NR^(C)R^(D), NR^(C)R^(D),NR^(c)C(O)R^(B), NR^(C)C(O)NR^(C)R^(D), NR^(C)C(O)OR^(A), S(O)R^(B),S(O)NR^(C)R^(D), S(O)₂R^(B), NR^(C)S(O)₂R^(B), and S(O)₂NR^(C)R^(D);wherein said cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or C₁₋₆alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy⁵, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), C(═NR^(g))NR^(c1)R^(d1),NR^(c1)C(═NR^(g))NR^(c1)R^(d1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); or R² and-L²-Cy² are linked together to form a group of formula:

wherein ring B is a fused aryl or fused heteroaryl ring, each optionallysubstituted with 1, 2, or 3 —W′—X′—Y′—Z′; R⁴ and R⁵ are independentlyselected from H, halo, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C₁₋₆haloalkyl, CN, and NO₂; or R⁴ and R⁵ together with the C atom to whichthey are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl orheterocycloalkyl ring, each optionally substituted by 1, 2, or 3substituents independently selected from halo, OH, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, alkoxyalkyl, cyanoalkyl,heterocycloalkyl, cycloalkyl, C₁₋₆ haloalkyl, CN, and NO₂; R⁶ is H, C₁₋₆alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; R⁷ and R⁸ are independentlyselected from H, halo, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, CN, and NO₂; or R⁷ and R⁸ together with the Catom to which they are attached form a 3, 4, 5, 6, or 7-memberedcycloalkyl or heterocycloalkyl ring, each optionally substituted by 1,2, or 3 substituent independently selected from halo, OH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, CN, and NO₂; R⁹is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; W, W′, and W″ areindependently absent or independently selected from C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO, CONR^(h), SO, SO₂,SONR^(h) and NR^(h)CONR^(i), wherein each of the C₁₋₆ alkylene, C₂₋₆alkenylene, and C₂₋₆ alkynylene is optionally substituted by 1, 2 or 3substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, andC₂₋₈ dialkylamino; X, X′, and X″ are independently absent orindependently selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, arylene, cycloalkylene, heteroarylene, andheterocycloalkylene, wherein each of the C₁₋₆ alkylene, C₂₋₆ alkenylene,C₂₋₆ alkynylene, arylene, cycloalkylene, heteroarylene, andheterocycloalkylene is optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₈alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR^(j), C(O)NR^(h)R^(i),amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino; Y, Y′, and Y″ areindependently absent or independently selected from C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO, CONR^(h), SO, SO₂,SONR^(h), and NR^(h)CONR^(i), wherein each of the C₁₋₆ alkylene, C₂₋₆alkenylene, and C₂₋₆ alkynylene is optionally substituted by 1, 2 or 3substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, andC₂₋₈ dialkylamino; Z, Z′, and Z″ are independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g))NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, N₃, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g))NR^(c2)R^(d2),NR^(c2)C(═NR^(g))NR^(c2)R^(d2), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein twoadjacent —W—X—Y—Z, together with the atoms to which they are attached,optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20membered heterocycloalkyl ring, each optionally substituted by 1, 2, or3 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)C(O)OR^(a3), C(═NR^(f1))NR^(c3)R^(d3),NR^(c3)C(═NR)NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),NR^(c3)S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3), aryl, cycloalkyl, heteroaryl,and heterocycloalkyl; wherein two adjacent —W′—X′—Y′—Z′, together withthe atoms to which they are attached, optionally form a fused 4-20membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring,each optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(g))NR^(c3)R^(d3), NR^(c3)C(═NR)NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),S(O)₂NR^(c3)R^(d3), aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;Cy³, Cy⁴, and Cy⁵ are independently selected from aryl, cycloalkyl,heteroaryl, and heteorcycloalkyl, each optionally substituted by 1, 2,3, 4, or 5 substituents independently selected from halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halosulfanyl, CN, NO₂, N₃,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4) C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), C(═NR^(g))NR^(c4)R^(d4),NR^(c4)C(═NR^(g))NR^(c4)R^(d4), P(R^(f4))₂, P(OR⁴)₂, P(O)R^(e4)R^(f4),P(O)OR^(e4)OR^(f4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),NR^(c4)S(O)₂R^(b4) and S(O)₂NR^(c4)R^(d4); R^(A) is H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylwherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo,and C₁₋₄ alkyl; R^(B) is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C₁₋₄alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, and C₁₋₄alkyl; R^(C) and R^(D) are independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, orC₂₋₄ alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄alkyl; or R^(C)and R^(D) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, and C₁₋₄alkyl; R^(a), R^(a1), R^(a2),R^(a3), and R^(a4) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy; R^(b), R^(b1), R^(b2), R^(b3), andR^(b4) are independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy; R^(c) and R^(d) are independentlyselected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; or R^(c)and R^(d) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy; R^(c1) and R^(d1) are independentlyselected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; or R^(c1)and R^(d1) together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group,each optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy; R^(c2) and R^(d2) are independentlyselected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, whereinsaid C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a4), C(O)R^(b4), S(O)₂R^(b3), alkoxyalkyl, and alkoxyalkoxy; orR^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl,heteroaryl, C(O)OR^(a4), C(O)R^(b4), S(O)₂R^(b3), alkoxyalkyl, andalkoxyalkoxy; R^(c3) and R^(d3) are independently selected from H, C₁₋₁₀alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; or R^(c3) andR^(d3) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy; R^(c4) and R^(d4) are independentlyselected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; or R^(c4)and R^(d4) together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group,each optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆ haloalkoxy; R^(e), R^(e1), R^(e2), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, andheterocycloalkylalkyl; R^(e), R^(f1), R^(f2), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; R⁹ isH, CN, and NO₂; R^(h) and R^(i) are independently selected from H andC₁₋₆ alkyl;  R^(i) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; m is 0, 1,2, 3, 4, 5, or 6; p is 0, 1,2, 3, or 4; q is 0, 1,2, 3, or 4; r is 0,1,2, 3, 4, 5, or 6; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4,with the proviso that when A is CH, then L¹ is other than CO or(CR⁴R⁵)_(u) wherein u is
 1. 74. A method of treating a disease in apatient, wherein said disease is associated with dysregulation of theHGF/c-MET signaling pathway, comprising administering to said patient atherapeutically effective amount of a compound of Formula I:

or pharmaceutically acceptable salt thereof or prodrug thereof, wherein:all the variables are as defined in claim
 73. 75. The method of claim73, or pharmaceutically acceptable salt thereof, wherein A is N.
 76. Themethod of claim 73, or pharmaceutically acceptable salt thereof, whereinCy¹ is heteroaryl optionally substituted by 1, 2, 3, 4, or 5 —W—X—Y—Z.77. The method of claim 73, or pharmaceutically acceptable salt thereof,wherein Cy² is aryl optionally substituted by 1, 2, 3, 4, or 5—W′—X′—Y′—Z′.
 78. The method of claim 73, or pharmaceutically acceptablesalt thereof, wherein L¹ is CH₂ or CH₂CH₂ or cycloalkylene.
 79. Themethod of claim 73, or pharmaceutically acceptable salt thereof, whereinL² is cycloalkylene or arylene.
 80. The method of claim 73, orpharmaceutically acceptable salt thereof, wherein R¹ is H.
 81. Themethod of claim 73, or pharmaceutically acceptable salt thereof, whereinR² is H.
 82. The method of claim 73, or pharmaceutically acceptable saltthereof, wherein —W—X—Y—Z is halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂,N₃, or OR^(a2).
 83. The method of claim 73, or pharmaceuticallyacceptable salt thereof, wherein —W′—X′—Y′—Z′ is halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, N₃, or OR^(a2).
 84. The method of claim 73, orpharmaceutically acceptable salt thereof, wherein the compound ofFormula I is Formula IIa or IIb:


85. The method of claim 73, or pharmaceutically acceptable salt thereof,wherein the compound of Formula I is Formula III:


86. The method of claim 73, or pharmaceutically acceptable salt thereof,wherein the compound of Formula I is Formula VIII:


87. The method of claim 73, wherein the compound of Formula I isselected from:2-(4-Fluorophenyl)-7-(4-methoxybenzyl)imidazo[1,2-b][1,2,4]triazine;2-(4-Fluorophenyl)-7-[1-(4-methoxyphenyl)cyclopropyl]imidazo[1,2-b]-[1,2,4]-triazine;6-(1-(2-(4-Fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)cyclopropyl)quinoline;6-(4-Fluorophenyl)-3-(4-methoxybenzyl)imidazo[1,2-a]pyrimidine;6-(4-Fluorophenyl)-3-(1-(4-methoxyphenyl)cyclopropyl)imidazo[1,2-a]pyrimidine;6-(1-(6-(4-Fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl)cyclopropyl)quinoline;2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-(4-Bromo-3-fluorophenyl)-7-[(4-methoxyphenyl)thio]imidazo[1,2-b][1,2,4]triazine;2-Fluoro-4-(3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidin-6-yl)-N-methylbenzamide;2-chloro-4-3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidin-6-yl-N-methylbenzamide;2-Fluoro-N-methyl-4-[3-(quinolin-6-ylthio)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-chloro-N-methyl-4-[3-(quinolin-6-ylthio)imidazo[1,2-a]pyrimidin-6-yl]benzamide;Methyl2-fluoro-4-[7-(quinolin-6-ylthio)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate;2-(4-Bromo-3-fluorophenyl)-7-(4-methoxyphenoxy)imidazo[1,2-b][1,2,4]triazine;3-(4-Methoxyphenoxy)-6-(4-methyl-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidine;6-(4-Bromophenyl)-3-(4-methoxyphenoxy)imidazo[1,2-a]pyrimidine;2-chloro-N-methyl-4-[3-(quinolin-6-yloxy)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-(4-bromophenyl)-3-[(4-methoxyphenyl)thio]imidazo[1,2-a]pyrimidine;2-(4-fluorophenyl)-7-[(4-methoxyphenyl)thio]imidazo[1,2-b][1,2,4]triazine;6-(1-{6-[3-Fluoro-4-(1-methyl-2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;6-{1-[6-(1H-Pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;6-{1-[6-(4-Methyl-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;N,N-Dimethyl-1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxamide;N-[1-(4-Methyl-1,3-thiazol-2-yl)ethyl]-1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxamide;N-Cyclohexyl-3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidine-6-carboxamide;3-(1-Quinolin-6-ylcyclopropyl)-N-(tetrahydrofuran-2-ylmethyl)imidazo[1,2-a]pyrimidine-6-carboxamide;N-Cyclobutyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-(1-{6-[4-(Azetidin-1-ylcarbonyl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;N,N-Dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide;N-(1-Benzylpyrrolidin-3-yl)-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(1-Pyridin-2-ylpiperidin-4-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(1-Pyridin-2-ylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-{1-[6-(4-[(3S)-3-Fluoropyrrolidin-1-yl]carbonylphenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;N-[1-(Methoxymethyl)cyclobutyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(1-Pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-[1-(6-{4-[(3-Pyridin-2-ylpyrrolidin-1-yl)carbonyl]phenyl}imidazo[1,2-a]pyrimidin-3-yl)cyclopropyl]quinoline;6-{1-[6-(4-[(3S)-3-(Pyridin-2-yloxy)pyrrolidin-1-yl]carbonylphenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;N-[2-(Pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-[1-Methyl-2-(pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(2-Phenoxyethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-Cyclopropyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(Pyridin-2-ylmethyl)-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N,N-Dimethyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-Methyl-3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-[(1S)-1-Methyl-2-(methylamino)-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-[(1R)-1-Methyl-2-(methylamino)-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;(3R)-1-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoyl}pyrrolidine-3-carbonitrile;Methyl4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}-piperazine-1-carboxylate;6-[1-(6-{6-[4-(Methylsulfonyl)piperazin-1-yl]pyridin-3-yl}imidazo[1,2-a]pyrimidin-3-yl)cyclopropyl]quinoline;N,N-Dimethyl-4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxamide;N-(1S)-1-[(Dimethylamino)carbonyl]-2-methylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-1-[(Dimethylamino)carbonyl]cyclobutyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide;N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide;N-(1S)-1-[(Cyclopropylamino)carbonyl]-2,2-dimethylpropyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide;N-[(1S)-2-(Dimethylamino)-1-methyl-2-oxoethyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide;N-[(1R)-2-(Dimethylamino)-1-methyl-2-oxoethyl]-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridine-2-carboxamide;6-(1-{6-[4-(2-Oxo-2-pyrrolidin-1-ylethoxy)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;1-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarbonitrile;N,N-Dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzenesulfonamide;Methyl2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzylcarbamate;N′-2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl-N,N-dimethylurea;(3R)-1-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl}pyrrolidin-3-ol;6-(1-{6-[3-Fluoro-4-(1H-pyrazol-1-ylmethyl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;3-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzyl}-1,3-oxazolidin-2-one;2-Fluoro-N-methyl-4-[7-(quinoxalin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;6-{1-[6-(4-Chloro-1H-pyrazol-1-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;6-{1-[6-(2-Methyl-1,3-thiazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;6-{1-[6-(1,3-Thiazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;3-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;(3S)-1-{3-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoyl}pyrrolidin-3-ol;2,5-Difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2,5-Difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-Cyclopropyl-2,5-difluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2,5-Difluoro-N-(trans-4-hydroxycyclohexyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;1-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}pyrrolidin-2-one;3-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-1,3-oxazolidin-2-one;Ethyl4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate;2-(4-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-1H-pyrazol-1-yl)-N,N-dimethylacetamide;5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-N-methylpyridine-2-carboxamide;5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-N,N-dimethylpyridine-2-carboxamide;6-(1-{6-[3-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;6-(1-{6-[1-(Tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;6-(1-{6-[1-(1-Benzylpyrrolidin-3-yl)-1H-pyrazol-4-yl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;6-{1-[6-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;N,N-Dimethyl-4-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxamide;4-{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}cyclohexanol;{4-[3-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}acetonitrile;N-Methyl-5-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}pyridine-2-carboxamide;6-{1-[2-(4-Pyrimidin-5-yl-phenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]cyclopropyl}quinoline;6-(1-{2-[4-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinoline;6-[1-(2-{4-[1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}imidazo[1,2-b][1,2,4]triazin-7-yl)cyclopropyl]quinoline;N,N-Dimethyl-5-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}pyridine-2-carboxamide;6-(1-{2-[4-(1H-Imidazol-1-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)-quinoline;2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-Cyclopropyl-2-fluoro-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-methyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[1-(methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-4-(7-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide;4-[7-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide;N-(Pyridin-2-ylmethyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-Cyclopropyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-Cyclobutyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-(1-Pyridin-2-ylcyclopropyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-(2-Hydroxy-1,1-dimethylethyl)-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[(1S)-1-Benzyl-2-hydroxyethyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;(3R)-1-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoyl}pyrrolidin-3-ol;4-(7-(1-(Quinolin-6-yl)cyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide;N-Cyclopropyl-N-methyl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[1-(Methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[1-(Methoxymethyl)cyclobutyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[(1S)-1-(Methoxymethyl)-2-methylpropyl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[4-(Methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;4-[7-(1-Quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-1,3-thiazol-2-ylbenzamide;N-Pyrimidin-4-yl-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[4-(Methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-{(1R)-1-[(Dimethylamino)carbonyl]-2-methylpropyl}-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-Cyclopropyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[1-(methoxymethyl)cyclopropyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydro-2H-pyran-4-yl)benzamide;(3R)-1-{2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoyl}pyrrolidin-3-ol;2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;6-{2-[3-Fluoro-4-(1H-imidazol-1-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-7-ylmethyl}quinoline;3-{2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}-1,3-oxazolidin-2-one;N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-{(1S)-1-[(Dimethylamino)carbonyl]-3-methylbutyl}-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-{(1R)-3-methyl-1-[(methylamino)carbonyl]butyl}-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-{(1R)-1-[(Dimethylamino)carbonyl]-3-methylbutyl}-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-[(1R)-1-(Azetidin-1-ylcarbonyl)-3-methylbutyl]-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;3-{4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}propanenitrile;4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-ylacetonitrile;2-{4-[7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}acetamide;Methyl4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate;2-Fluoro-N-[(1S,2S)-2-hydroxycyclopentyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(2-hydroxyethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[1-(methoxymethyl)cyclobutyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-(Cyclopropylmethyl)-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-N-(tetrahydro-2H-pyran-4-ylmethyl)benzamide;N-[2-(Dimethylamino)ethyl]-2-fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(2-piperidin-1-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(pyridin-2-ylmethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(pyridin-3-ylmethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(pyridin-4-ylmethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(2-pyridin-2-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(1-pyridin-3-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(1-pyridin-4-ylethyl)-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[1-(hydroxymethyl)cyclopentyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-methyl-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;N-Cyclopropyl-2-fluoro-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-[1-(methoxymethyl)cyclopropyl]-4-[7-(1-quinolin-6-ylethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;2-Fluoro-N-(2-methoxy-1-methylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-{1-[6-(3-Fluoro-4-[(3S)-3-fluoropyrrolidin-1-yl]carbonylphenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline;2-Fluoro-N-(pyridin-2-ylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-(1-pyridin-2-ylcyclopropyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-(1-pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide;2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-(tetrahydrofuran-2-ylmethyl)benzamide;N-Cyclopropyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-[(1S)-1-(methoxymethyl)-2-methylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-methyl-N-2-[methyl(pyridin-2-yl)amino]ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Chloro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Chloro-N-cyclopropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-N-(tetrahydrofuran-3-yl)benzamide;2-Chloro-N-(1-pyridin-2-ylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-(1-{6-[4-(Azetidin-1-ylcarbonyl)-3-chlorophenyl]imidazo[1,2-a]pyrimidin-3-yl}cyclopropyl)quinoline;2-Chloro-N-(1-pyridin-2-ylpyrrolidin-3-yl)-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Chloro-N-[1-methyl-2-(pyridin-2-yloxy)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Chloro-N-(1S)-1-[(dimethylamino)carbonyl]-2-methylpropyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Cyclopropyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one;2-Ethyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one;2-(2-Methoxy-1-methylethyl)-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one;2-(Pyridin-2-ylmethyl)-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one;2-Methyl-5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]isoindolin-1-one;N-Ethyl-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide;N-(1-Pyridin-2-ylethyl)-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide;N-[1-Methyl-2-(pyridin-2-yloxy)ethyl]-1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxamide;2-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-2-hydroxy-N-methylacetamide;2-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}-2-hydroxy-N,N-dimethylacetamide;N-(3-[2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)-N′-ethylurea;2-(2,3-Dichlorophenyl)-7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-3-amine;2,3-Difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;6-Difluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzenesulfonamide;N,N-Dimethyl-2-{3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-yl}acetamide;N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-[2-(Dimethylamino)-1-methyl-2-oxoethyl]-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;N-(2-Azetidin-1-yl-1-methyl-2-oxoethyl)-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-2-[(3R)-3-methoxypyrrolidin-1-yl]-1-methyl-2-oxoethyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzamide;2-Fluoro-N-[(1-hydroxycyclopropyl)methyl]-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide;Methyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate;Ethyl4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate;(1-Acetyl-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrile,or pharmaceutically acceptable salt thereof.
 88. The method of claim 73,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of claim 73, orpharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 89. The method of claim 73, whereinsaid cancer is gastric cancer.
 90. The method of claim 73, wherein saidcancer is cancer of the kidney.
 91. The method of claim 73, wherein saidcancer is liver cancer.
 92. The method of claim 73, wherein said canceris lung cancer.
 93. The method of claim 73, wherein said cancer isglioblastoma.